Article

ISSN 0006-2979, Biochemistry (Moscow), 2026, Vol. 91, No. 5, pp. 733-769 © Pleiades Publishing, Ltd., 2026.

733

REVIEW

Metabolic Reprogramming

of Astrocytes and Microglia as a Driver

and Therapeutic Target in Epileptogenesis

Maria V. Zakharova

, Anna A. Kovalenko

, Yuliy A. Gorgul

Aleksandr P. Schwarz

, Olga E. Zubareva

, Adelia R. Kharisova

Georgy P. Diespirov

, and Aleksey V. Zaitsev

1,a

Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences,

194223 Saint-Petersburg, Russia

e-mail: aleksey_zaitsev@mail.ru

Received March 19, 2026

Revised April 18, 2026

Accepted April 21, 2026

Abstract— Metabolic reprogramming of astrocytes and microglia is considered a significant component of

epileptogenesis, associated with the development of neuronal network hyperexcitability, neuroinflammation,

and oxidative stress. This review analyzes key mechanisms of glial dysfunction, such as the shift toward

aerobic glycolysis (the Warburg effect), mitochondrial disturbances, and generation of reactive oxygen spe-

cies. These processes are regulated by the Wnt/GSK3β and mTOR signaling cascades, forming a vicious

cycle of energy deficit, NLRP3 inflammasome activation, and excitotoxicity. Particular attention is given

to strategies for correcting glial metabolism. The greatest therapeutic interest lies in systemic approaches

that correct metabolism (ketogenic diet, GLP-1 and PPAR receptor agonists) and high-precision technolo-

gies for selective modulation of glial functions (RNA therapy, nanodelivery). Targeted intervention in glial

metabolism opens ways to the development of anti-epileptogenic drugs capable of modifying the disease

course rather than merely alleviating the symptoms. However, translation of these approaches into clinical

practice requires clarification of therapeutic windows for the intervention and development of biomarkers

of glial status.

DOI: 10.1134/S0006297926600857

Keywords: astrocytes, microglia, epileptogenesis, neuroinflammation, oxidative stress, glucose metabolism,

lactate shuttle

* To whom correspondence should be addressed.

INTRODUCTION

Epilepsy is a group of chronic neurological dis-

orders characterized by recurrent, uncontrolled sei-

zures  [1]. Its development is driven by epileptogen-

esis – a continuous, dynamic, multifactorial process

conventionally divided into three phases: (i)  the initi-

ating phase, which occurs following brain injury (e.g.,

traumatic brain injury, infection, stroke, tumor) or

arises from genetic predisposition or a combination

of these factors; (ii)  the latent phase, during which

compensatory and pathological rearrangements take

place at the molecular, cellular, and structural levels;

and (iii)  the chronic phase, characterized by the man-

ifestation of spontaneous recurrent seizures (SRSs).

Recurrent seizure activity can exacerbate pathological

changes, leading to disease progression and pharma-

coresistance  [2-4].

Traditional concepts attribute the development

of epilepsy to an imbalance between the excitatory

and inhibitory systems in the brain  [5,  6]. Most an-

tiepileptic medications aim to suppress the seizure

activity by modulating ion channels or neurotrans-

mitter systems. However, such therapy mainly al-

leviates symptoms and does not prevent epilepto-

genesis  [7-9]. Reflecting this, the term “antiepileptic

ZAKHAROVA et al.734

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

drugs” is being increasingly replaced by “antiseizure

drugs” in the current literature  [9]. Moreover, direct

interference with neuronal pathways often caus-

es cognitive and psychoemotional side effects  [10].

These challenges highlight the need to identify new

targets, with glial cells emerging as a promising

avenue.

Recent studies confirm the key role of astrocytes

and microglia in the pathogenesis of epilepsy, includ-

ing both epileptogenesis and progression of seizure

activity  [11,  12]. In response to seizure episodes, glial

cells undergo significant morphological and molecu-

lar changes  [13,  14]. Given the functional differences,

glial reactive states have traditionally been classified

as neurotoxic (M1 in microglia, A1 in astrocytes) and

neuroprotective (M2 and A2, respectively)  [15,  16].

The M1/A1 phenotypes are associated with increased

expression of proinflammatory cytokines and produc-

tion of reactive oxygen species (ROS) and reactive ni-

trogen species (RNS), whereas M2/A2 phenotypes are

characterized by predominantly anti-inflammatory

and trophic signaling. However, in recent years, this

dichotomous model has been criticized due to the

revealed diversity of glial reactive states  [15,  17,  18],

which complicates their unambiguous classification

as exclusively neurotoxic or neuroprotective  [11].

Accordingly, in this review, the designations M1/M2

and A1/A2 were used solely as conventional descrip-

tors of signaling polarity, while the focus was on the

evaluation of specific metabolic pathways that regu-

late glial functions and determine their contribution

to epileptogenesis.

Metabolic reprogramming is a central component

of abnormal glial activation in epileptogenesis. In as-

trocytes, it can include impaired lactate shuttling  [19],

reduced oxidative metabolism, and a shift toward

the synthesis of proinflammatory metabolites  [20].

In microglia, the switch to glycolytic metabolism di-

rectly fuels the proinflammatory phenotype  [21], en-

hancing the production of interleukin-1β (IL-1β) and

other cytokines while simultaneously promoting ROS

generation, which leads to oxidative stress and neu-

ronal damage. Collectively, these metabolic changes

in glial cells form a vicious cycle linking hyperexcit-

ability, neuroinflammation, and neurodegeneration.

Strategies aimed at reprogramming glial metabolism

represent a promising avenue for disease-modifying

therapy of epilepsy.

This review systematizes current knowledge on

the metabolic reprogramming of astrocytes and mi-

croglia as a key driver of epileptogenesis, and evalu-

ates the potential of its targeted correction. We also

examined pathological changes in glycolysis, oxida-

tive phosphorylation, ROS generation, and neuroin-

flammation and discussed experimental approaches

for developing disease-modifying therapy.

ROLE OF GLIAL GLYCOLYSIS IN METABOLIC

REPROGRAMMING DURING EPILEPTOGENESIS

Glucose is the main energy substrate of the brain

under physiological conditions, necessary for main-

taining ion homeostasis and the transmembrane po-

tential of neurons. Metabolic interactions between

astrocytes and neurons play a critical role in the en-

ergy supply of neuronal activity, mainly via the lac-

tate shuttle. According to this concept, the uptake of

synaptic glutamate by astrocytes stimulates glycolysis,

leading to lactate synthesis and release. Subsequent

uptake of lactate by neurons and its oxidation in the

tricarboxylic acid (TCA) cycle provide efficient energy

supply, especially during periods of increased func-

tional load, because lactate oxidation involves fewer

metabolic steps, as it bypasses the energy-consuming

glycolysis and does not require prior phosphoryla-

tion, thereby accelerating the entry of carbon units

into the TCA cycle  [22].

During epileptogenesis, this tightly regulated

mechanism undergoes fundamental reprogramming.

Periods of seizure activity are associated with a sig-

nificant elevation in the extracellular glutamate, lead-

ing to intensification of its uptake by astrocytes  [23].

This process, in turn, promotes glycolysis in astroglia,

resulting in pronounced fluctuations in local glucose

and lactate concentrations. Under the high energetic

demands of seizures, lactate produced in astrocytes

becomes a critical alternative energy source for neu-

rons  [24], thus fostering a state of pathological meta-

bolic dependence. This shift is similar to the Warburg

effect, characterized by prioritization of glycolysis

despite sufficient cellular oxygenation  [25]. It is im-

portant to note that although this metabolic shift was

originally described for cancer cells, it can also occur

in normal cells, such as T  helper cells, macrophages,

actively proliferating stem cells, microglia, and astro-

cytes  [26]. Clinically, these alterations are reflected in

temporal lobe epilepsy, where seizures are associated

with increased glucose uptake and metabolism  [27],

while interictal periods show decreased glucose uti-

lization  [28].

As mentioned earlier, the molecular basis of

pathological metabolic reprogramming is the inten-

sification of glycolysis despite normal oxygen avail-

ability. A key role in this process is played by ca-

nonical Wnt signaling  [29]. Its activation leads to the

inhibition of glycogen synthase kinase  3β (GSK3β),

resulting in stabilization and accumulation of β-cat-

enin, as well as reduction in the activity of tuberous

sclerosis complex  2 (TSC2)  [30]. Elevated β-catenin

levels induce transcription of genes encoding key

metabolic enzymes such as hexokinase  2 (HK2), pyru-

vate kinase  M2 (PKM2), and lactate dehydrogenase  A

(LDHA), thereby shifting metabolism toward glycolysis

METABOLIC REPROGRAMMING OF GLIA IN EPILEPTOGENESIS 735

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

and creating a Warburg-like effect. This phenomenon

has been demonstrated in the pilocarpine mouse mod-

el  [29]. In that study, increased mRNA and protein

levels of HK2 and PKM2 were observed on the third

day after status epilepticus induction, indicating gly-

colysis activation. By the fifth day, LDHA expression

was upregulated as well, suggesting that this stage

of epileptogenesis was marked by a metabolic shift

toward glycolysis, rather than a general increase in

metabolic activity. Intensification of glycolysis leads

to a decrease in intracellular AMP levels, which in-

hibits AMP-activated protein kinase (AMPK)  [31].

Concurrent inhibition of GSK3β and AMPK, together

with reduced TSC2 activity, results in hyperactivation

of the mTOR signaling pathway. Activation of mTOR

signaling is a well-established pro-inflammatory and

epileptogenic factor that increases the propensity of

neuronal networks to generate seizure episodes  [32],

thereby establishing a vicious cycle of metabolic re-

programming and hyperexcitability.

Such dynamics indicate that glial glycolysis is

not merely an adaptive response to epileptic activi-

ty but may actively contribute to the maintenance of

the neuronal network hyperexcitability (Fig.  1). Con-

sequently, the key glycolytic enzymes and regulatory

pathways in glial cells represent potential therapeutic

targets for modulating epileptogenesis and associated

metabolic disturbances. However, because glycolysis

is a universal cellular process, interventions target-

ing this pathway will face significant translational

constraints. Targeting the key steps of glycolysis has

been suggested as a strategy for metabolic control of

epileptic hyperexcitability (Table  1). The most promis-

ing candidates for therapeutic targets are HK2, PKM2,

and LDHA.

HK2 is expressed predominantly in the microglia

and astroglia and plays an essential role in the regula-

tion of inflammation  [33]. In astrocytes, it participates

in epileptogenesis by promoting glycolysis and lactate

production– a key energy substrate in neurons during

hyperexcitation  [34,  35]. This creates a pathological

metabolic loop that sustains neuronal hyperexcitabil-

ity and propagation of epileptiform activity. Inhibi-

tion of HK2 (e.g., with 2-deoxyglucose, 2-DG) disrupts

lactate shuttling and suppresses epileptogenesis  [36].

2-DG, a structural analogue of glucose, enters cells via

glucose transporters (GLUT) and is phosphorylated

by HK2 to 2-deoxyglucose-6-phosphate (2-DG6P)  [37].

This metabolite blocks glycolysis through two mecha-

nisms: competitive inhibition of phosphoglucose isom-

erase and allosteric suppression of HK2 via negative

feedback  [38]. Additionally, 2-DG6P stimulates the pen-

tose phosphate pathway, enhancing NADPH synthesis

and shifting metabolism toward antioxidant processes.

PKM2, the predominant pyruvate kinase iso-

form in glial cells, regulates epileptogenesis through

Fig.  1. Pathological cycle of energy metabolism dysregula-

tion in astrocytes. Seizure-driven accumulation of extracel-

lular glutamate stimulates glycolysis in astrocytes. Wnt ac-

tivation leads to the inhibition of GSK3β, resulting in the

stabilization and accumulation of β-catenin and decreased

TSC2 activity, which induces the transcription of key glyco-

lytic enzymes HK2, PKM2, and LDHA. Enhanced glycolysis

leads to increased production of lactate. Lactate is shuttled

to neurons, where it fuels the TCA cycle, thereby promoting

neuronal hyperexcitability. Furthermore, intensified glycol-

ysis results in the inhibition of AMPK, which, together with

GSK3β inhibition and reduced TSC2 activity, activates the

proinflammatory mTOR signaling pathway, further exacer-

bating hyperexcitability. Upward red arrows indicate in-

creases in concentration, expression, or activity; downward

red arrows indicate decreases; solid black arrows denote

established mechanisms supported by the published reports;

dashed black arrows represent interactions proposed based

on literature analysis.

ZAKHAROVA et al.736

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

Table 1. Effects of pharmacological regulation of key glycolytic enzymes in models of seizures and epilepto-

genesis

Treatment Seizure induction

Subject

Analysis time

Biochemical

effects

Functional effects References

Effect on HK2

2-DG

10 mM

in vitro studies

in the hippocampus

P10-P17

Sprague-Dawley rats

not studied significant reduction

in the frequency of epileptiform

discharges;

suppression of abnormal network

epileptiform activity

[51]

2-DG

10 mM

invitro

P10-P13 or P28-P120

Sprague-Dawley rats

not studied reduction of interictal epileptiform

discharges

[52]

2-DG

L – 100  mg/kg

M – 250  mg/kg

H – 500  mg/kg

i.p. 30  min prior

to pilocarpine

pilocarpine-kindling

male C57BL/6 mice

analysis at 4  h,

and 1, 7, 30, 60  days

after seizures

M and H

enhanced the

expression

of Kir6.1 and

Kir6.2 in the

hippocampus

increased seizure latency,

decreased seizure duration, and

reduced seizure severity score.

In groups M and H, seizure

latency was significantly longer,

seizure duration was significantly

shorter, and seizure severity score

was significantly lower than

in the seizure group

[53]

2-DG

300  mg/kg, i.p.

On days 20 through

28 post-seizures

kainic acid

(0.8  nmol, i.h.)

adult male

NMRI mice

immediately

after treatment

not studied partial recovery of behavioral

impairments

[54]

Effect on LDHA

Stiripentol (300  mg/kg)

Isosafrole

(100-300  mg/kg)

kainic acid

mice

not studied reduction of high-voltage spikes

in the hippocampus

[48]

Stiripentol 150, 250,

350  mg/kg, i.p.

1  hour before seizures

PTZ (100  mg/kg)

LiCl/pilocarpine

(30  mg/kg)

male Wistar rats

P21 and P75

not studied anticonvulsant properties

in both models and both ages;

more effective at P21

[55]

Note. i.p., intraperitoneally; i.h., injection into hippocampus

switching metabolic pathways  [39]. Unlike the neuro-

nal PKM1 isoform, PKM2 controls glycolysis via oligo-

merization: PKM2 tetramers maintain glycolytic flux,

whereas its dimers redirect metabolites into alterna-

tive pathways (pentose phosphate pathway, etc.), pro-

moting biosynthetic and antioxidant processes  [40].

Under pathological conditions, PKM2 triggers a cycle

of self-sustained glial hyperactivity, as lactate accu-

mulation stimulates lactylation (a poorly understood

intermediate post-translational modification  [41])

of histone H4K12, which results in the upregula-

tion of glycolysis-associated genes, e.g., those encod-

ing hypoxia-inducible factor-1α (HIF-1α), PKM2, and

LDHA  [42], further amplifying neuronal hyperexcit-

ability  [43]. Experimental inhibition of PKM2 demon-

strated neuroprotective effects, including reduction

of cognitive deficits and tissue damage in neurolog-

ical disorders  [44,  45]. Although no PKM2 inhibitors

are used in clinic, the enzyme remains a promising

target for epilepsy therapy. The suggested strategy

is aimed but at modulating PKM2 oligomeric state

(tetramer↔dimer) in order to correct pathological

METABOLIC REPROGRAMMING OF GLIA IN EPILEPTOGENESIS 737

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

metabolic and transcriptional programs in glial cells

rather than complete suppression of its activity.

LDHA plays a key role in the lactate shuttle by

catalyzing the interconversion of lactate and pyru-

vate  [46]. Inhibition of this enzyme leads to disrup-

tion of the lactate shuttle and consequently reduces

ATP production  [47]. The resulting decrease in the in-

tracellular ATP content activates ATP-sensitive potas-

sium channels, leading to the efflux of intracellular

potassium and hyperpolarization of neurons, thereby

reducing their excitability  [48]. Among therapeutic

agents targeting LDHA, oxamate  [48] and stiripen-

tol  [49] are the most promising. Oxamate, which is

a pyruvate analogue, acts as a competitive inhibitor

of LDHA  [50]; the molecular mechanism of action of

stiripentol remains unclear.

OXIDATIVE STRESS IN EPILEPTOGENESIS

AND TARGETED THERAPY STRATEGIES

ROS and RNS are generated as byproducts of

cellular metabolism under physiological conditions.

While they normally participate in cell signaling,

their excessive production can lead to pathological

outcomes  [56]. Under normoxic conditions, pyru-

vate primarily undergoes oxidative decarboxylation

to form acetyl-CoA, which enters the TCA cycle to

support oxidative phosphorylation. Although this

process is essential for ATP production, it is also a

major source of ROS and RNS  [57]. ROS comprise a

group of partially reduced oxygen derivatives, includ-

ing superoxide anion (O

•

−

), hydroxyl radical (•OH),

peroxyl radicals (ROO•), alkoxyl radicals (RO•), and

hydrogen peroxide (H

). At physiological levels,

these oxygen species modulate various physiological

processes, including cell proliferation and differentia-

tion, immune responses, and apoptosis  [58]. However,

when produced in excess, ROS can trigger patholog-

ical effects. In mitochondria, superoxide radicals are

generated through the reduction of molecular oxygen

during electron transfer. Although hydrogen peroxide

(a byproduct of this reaction) is not a free radical, it

can be converted into hydroxyl radicals, which are

among the most dangerous forms of ROS. The reac-

tion between superoxide and nitric oxide (NO) leads

to the formation of peroxynitrite (ONOO

−

), a highly

reactive molecule capable of inducing lipid peroxida-

tion, protein nitration, and DNA damage  [56].

From a perspective of energy metabolism, ac-

tivation of astrocytes and microglia can lead to an

additional increase in glucose utilization through

two mechanisms. First, pyruvate, the end product of

glycolysis, may be redirected from utilization in the

TCA cycle toward lactate synthesis (Warburg-like ef-

fect, see the previous section). This shift is particu-

larly pronounced in proinflammatory glial activation,

which is associated with the elevated production of

proinflammatory cytokines and ROS/RNS. The second

possible pathway is the intensification of TCA cy-

cle and oxidative phosphorylation in mitochondria,

which is more typical of the anti-inflammatory state

of glial cells associated with the activation of neuro-

protective mechanisms. In microglia, glycolysis acti-

vation is considered one of the earliest signs, as well

as a trigger, of proinflammatory activation  [57]. How-

ever, in astrocytes, the relationship between metabol-

ic and transcriptomic profiles remains largely unex-

plored.

In resting microglia, unlike astrocytes, almost

all pyruvate is funneled into the TCA cycle, where-

as upon proinflammatory activation in epilepsy, the

activity of key enzymes of oxidative metabolism (ac-

onitase, malate dehydrogenase, and succinate dehy-

drogenase) is reduced. At the same time, the activity

of glycolytic enzymes increases, resulting in the met-

abolic shift toward glycolysis, accompanied by lactate

accumulation, downregulation of the TCA cycle, and

succinate accumulation  [57,  59]. In the presence of ex-

cess succinate (a substrate for the electron transport

chain complex  II), electrons transferred from succi-

nate reduce ubiquinone to ubiquinol. Electrons can

then be transferred in reverse from ubiquinol back to

complex  I, leading to NAD

reduction to NADH. This

reverse electron flow through complex  I is associat-

ed with increased ROS production, particularly at the

flavin mononucleotide site of complex  I  [58].

Thus, the metabolic shift toward glycolysis and

disturbances in mitochondrial metabolism contribute

substantially to ROS accumulation. Also, many en-

zymes [lipoxygenases, cyclooxygenases, NO synthase

(NOS), NADPH oxidase] upregulated during proin-

flammatory activation of glial cells or under the in-

fluence of proinflammatory cytokines also produce

free radical intermediates or end products. Oxida-

tive stress in epileptogenesis has been confirmed in

both experimental and clinical studies  [60]. ROS and

RNS are generated in enzymatic and non-enzymatic

reactions, as well as byproducts of aerobic metabo-

lism  [61]. Mitochondria are one of the main sources

of ROS: mitochondrial DNA damage and increased

production have been demonstrated in the ka-

inate model  [62]. In acquired epilepsy models, inhibi-

tion of α-ketoglutarate dehydrogenase, mitochondrial

aconitase, or complex I of the mitochondrial electron

transport chain has been shown to further enhance

radical generation  [63].

Antioxidants can mitigate mitochondrial oxida-

tive stress  [56]. Several experimental studies have

demonstrated the efficacy of antioxidant administra-

tion during the latent phase of experimental epilepsy

models or its ability to reduce animal susceptibility

ZAKHAROVA et al.738

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

to convulsants  [64-66]. While antioxidants effectively

prevent memory impairment and neuronal death  [64,

65, 67-70], they do not typically affect spontaneous

seizures  [67,  68,  71]. Furthermore, when used as

monotherapy, antioxidants may exhibit pro-oxidant

effects under specific conditions  [72], suggesting that

combination therapy may be a safer and more effec-

tive approach. Multicomponent antioxidant treatment

regimens provide a broad spectrum of protective

effects by reducing oxidative stress and modulat-

ing neuroinflammatory and neurotransmitter path-

ways  [56].

ROS generation by non-mitochondrial sourc-

es increases during seizure development, particu-

larly via activities of NADPH oxidase and xanthine

oxidase  [73]. Administration of the NADPH oxidase

inhibitor apocynin for 7  days prior to induction of

status epilepticus by pilocarpine proved effective in

reducing both ROS formation and neurodegenera-

tion  [64]. Kim et  al.  [74] demonstrated that apocynin

administration following pilocarpine-induced seizures

reduced ROS production and lipid peroxidation, as

well as decreased neurodegeneration in the rat hip-

pocampus. Furthermore, this treatment reduced sei-

zure-induced disruption of the blood–brain barrier

(BBB) and decreased neutrophil infiltration and mi-

croglial activation  [74]. Other studies have shown that

kainate-induced NADPH oxidase activation closely

paralleled microglial activation in the rat hippocam-

pus  [75], highlighting the important role of microglia

in seizure-associated ROS production.

Another enzyme extensively studied in the con-

text of epilepsy is NOS. Neuronal NOS (nNOS) is the

most studied isoform of this enzyme as a target for

preventing neurodegeneration, whereas inducible

NOS (iNOS) has recently emerged as a promising

target in epilepsy treatment  [76]. Increased nNOS

levels were observed in rat hippocampal astrocytes

following electrically induced status epilepticus  [77].

Kainate-induced seizures led to elevated nNOS levels

in neurons and iNOS in glial cells  [78]. Meskinimood

et  al. demonstrated that both nNOS and iNOS con-

tribute to the anticonvulsant effect of morphine  [79].

Inhibition of NOS activity by NG-nitro-L-arginine in-

creased the seizure threshold in mice  [80], further

supporting the role of NOS inhibition in the anticon-

vulsant effects. Aminoguanidine, an iNOS inhibitor,

suppressed pentylenetetrazole (PTZ)-induced seizures

and SRSs in the pilocarpine model of epilepsy in

mice  [81]. The highly selective iNOS inhibitor 1400W

significantly reduced the number of SRS episodes in

the kainate model of epilepsy in rats  [82], as well as

downregulated expression of astroglial and microg-

lial markers and ameliorated neurodegeneration in

the hippocampus, amygdala, and entorhinal cortex

in rats  [82].

Another important target is HIF-1α, which plays a

key role in cellular adaptation to oxidative stress  [83].

Stabilization of HIF-1α in the epileptic focus integrates

hypoxia, oxidative stress, and pathological metabolic

reprogramming. Direct pharmacological inhibition of

HIF-1α with PX-478 in a chronic PTZ-induced mouse

model of epilepsy not only reduced seizure severity

and duration but also exerted a neuroprotective ef-

fect. This protective effect was mediated by suppres-

sion of the HIF-1α/heme oxygenase-1 (HO-1) pathway,

resulting in reduced oxidative stress and inhibition of

ferroptosis in hippocampal neurons  [84]. Conversely,

in the acute phase, HIF-1α may exert adaptive effects

through activation of the Notch signaling pathway. Di-

rect interaction of HIF-1α with the Notch intracellular

domain (NICD) stimulates neurogenesis, whereas inhi-

bition of HIF-1α (with 2-methoxyestradiol) and Notch

(with DAPT) abolishes this beneficial effect  [85].

It is important to note that oxidative stress and

neuroinflammation, another important pathogenetic

mechanism of epileptogenesis, can mutually reinforce

each other through both metabolic dysregulation and

associated macromolecular damage, as well as through

specific signaling pathways [86-88]. Accordingly, si-

multaneous suppression of neuroinflammation and

oxidative stress may exert a more pronounced effect

by acting on different components of interconnected

pathophysiological cascades. However, most combina-

tion therapy strategies have been focused on pairing

classical antiseizure drugs with antioxidants. In par-

ticular, in a PTZ-induced epilepsy model, therapy with

valproate and the antioxidant astaxanthin produced

a significant neuroprotective effect, accompanied by

reduced oxidative stress, increased glutathione lev-

els, and decreased tumor necrosis factor (TNF) con-

tent  [89]. The combination of valproate and vitamin  E

also demonstrated anti-inflammatory and antioxidant

effects in a seizure model induced by PTZ and cyper-

methrin  [90].

It should be emphasized that generation of free

radicals in glial cells is not inherently pathological.

Under physiological conditions, astrocytes and mi-

croglia produce moderate amounts of superoxide

and hydrogen peroxide that perform signaling func-

tions  [91,  92]. Furthermore, NO released by neurons

during glutamatergic transmission inhibits mitochon-

drial complex  IV in astrocytes, leading to glycolysis

activation and release of lactate that can be taken

up by neurons  [93]. Different types of ROS can exert

vasodilatory or vasoconstrictive effects on cerebral

vasculature  [94]. Consequently, excessive or non-se-

lective suppression of ROS/RNS (e.g., by high doses

of classical antioxidants) may disrupt physiological

neuro-glial signaling and impair metabolic support

of neurons. For this reason, classical antioxidants

are viewed as less promising therapeutic options than

METABOLIC REPROGRAMMING OF GLIA IN EPILEPTOGENESIS 739

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

Table 2. Pharmacological modulation of antioxidant systems in models of seizures and epileptogenesis

Treatment Seizure induction

Subject

Analysis time

Biochemical effects Functional effects References

Melatonin

20, 40, 80  μg, i.c.v.

10  min before penicillin

penicillin

(200  IU, i.cort.)

adult female Wistar rats

not studied 40 and 80  μg increased latency to

epileptiform activity; reduced spike

frequency and spike-wave activity

[95]

Melatonin

10  mg/kg, s.c.

3  h after seizures for 3  days,

then 8  weeks in drinking

water

kainic acid

adult male Wistar rats

chronic phase

restored hippocampal 5-HT levels increased latency to first SRS

and reduced their frequency

only during treatment; reduced

hyperactivity, depressive-like

behavior, and hippocampal-

dependent working memory deficit;

reduced neurodegeneration in CA1

[96]

Melatonin

20  mg/kg for 15  days

before PTZ

PTZ (60 mg/kg, i.p.)

mice

immediately after seizures

not studied increased latency and reduced

seizure duration

[97]

Melatonin

50, 100, 200  mg/kg, i.p.

15  min before test

maximal electroshock (MES),

6  Hz, PTZ

male Swiss albino mice

not studied increased seizure threshold [98]

Vitamins

Vitamin E

250  mg/kg, i.p.

3  h after seizures,

then once daily for 4  days

kainic acid (15  mg/kg, i.p.)

adult male

Sprague-Dawley rats

4  days after seizures

reduced hippocampal lipid peroxidation reduced astrocytosis and

microglial activation, decreased

neurodegeneration and dendritic

spine loss in hippocampus

[70]

Vitamin E

250  mg/kg, i.p.

once daily for 4  days, then

2  mg/kg until day  15

kainic acid (10  mg/kg, i.p.)

adult male

Sprague-Dawley rats

15  days after seizures

restored claudin protein level;

suppressed neuroinflammation: reduced

TNF, IL-1β, glial fibrillar acidic protein

(GFAP), IBA-1 (ionized calcium-binding

adapter molecule  1), and increased IL-6

restored population spike count

and latency to epileptiform

network activity to control levels;

prevented neuronal death

[99]

Vitamin E

200  mg/kg, i.p.

30  min before each PTZ

injection

PTZ kindling (35  mg/kg, i.p.)

adult male

Sprague-Dawley rats

after treatment completion

reduced 15-lipoxygenase (15-LOX)

expression, suppressed malondialdehyde

(MDA) and iron accumulation,

downregulated glutathione peroxidase  4

(GPX4) and expression and lowered

glutathione (GSH) levels

reduced seizure stage, latency,

and number of seizures

[100]

ZAKHAROVA et al.740

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

Table 2 (cont.)

Treatment Seizure induction

Subject

Analysis time

Biochemical effects Functional effects References

Vitamin E

200  mg/kg, i.p.

30  min before pilocarpine

pilocarpine (400  mg/kg, i.p.)

adult male Wistar rats

first 24  h after seizures

reduced lipid peroxidation and nitrite

content; increased superoxide dismutase

(SOD) and catalase (CAT) activity

in hippocampus

not studied [101]

Vitamin E

200 and 400  mg/kg, i.p.

before pilocarpine

pilocarpine (400  mg/kg, i.p.)

adult male Wistar rats

not studied anticonvulsant effect [102]

Vitamin C

250  mg/kg, i.p.

30  min before pilocarpine

pilocarpine (400  mg/kg, s.c.)

two-month-old male

Wistar rats

first 24 h after seizures

reduced lipid peroxidation; increased

hippocampal catalase activity

increased latency to first seizure;

reduced mortality

[66]

Vitamin C

30  min before pilocarpine

a)  30  mg/kg, i.p.

b)  100  mg/kg, i.p.

c)  300  mg/kg, i.p.

PTZ (1.8  μmol/striatum)

adult male Wistar rats

3 days after seizures

a)  prevented increase in protein

carbonylation in striatum;

b)  no effect;

c)  protected against protein

carbonylation and inhibition

of Na

-ATPase in striatum

a)  no change in PTZ-induced

seizures;

b)  proconvulsant effect (potentiated

seizure duration);

c)  anticonvulsant effect

[103]

Vitamin C

250  mg/kg, i.p.

10  min before convulsant

a)  pilocarpine

(300  mg/kg, i.p.);

b)  kainic acid (10  mg/kg, i.p.);

c)  PTZ (75  mg/kg, s.c.)

adult Sprague-Dawley rats

first 24  h after seizures

no effect on GSH levels a)  anticonvulsant effect;

b)  no effect;

c)  reduced mortality

[104]

Vitamin C

500  mg/kg, i.p.

30  min before pilocarpine

pilocarpine (400  mg/kg, i.p.);

adult male Wistar rats

first 24  h after seizures

not studied increased latency to first seizure;

reduced seizure frequency and

mortality; prevented spatial and

working memory impairment in

Morris water maze test; reduced

hippocampal neuronal damage

[105]

Vitamin C

250  mg/kg, s.c.

2  h before PTZ

PTZ kindling (50  mg/kg, s.c.,

7  days)

adult Sprague-Dawley rats

not studied attenuated seizures; reduced

mortality and neurodegeneration

[106]

METABOLIC REPROGRAMMING OF GLIA IN EPILEPTOGENESIS 741

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

Table 2 (cont.)

Treatment Seizure induction

Subject

Analysis time

Biochemical effects Functional effects References

Vitamin C

250 and 500  mg/kg, i.p.

before pilocarpine

pilocarpine (400  mg/kg, i.p.)

adult male Wistar rats

1  day after seizures

not studied anticonvulsant effect [102]

Polyphenols

Curcumin

50, 100, 200  mg/kg, p.o. for

3  days before pilocarpine

Li (3  mEq/ml/kg)-pilocarpine

(20  mg/ml/kg, s.c.)

adult Sprague-Dawley rats

immediately after seizures

ameliorated oxidative damage

in hippocampus and striatum

increased seizure latency; reduced

seizure percentage, frequency

and intensity;

attenuated cognitive dysfunction

[67]

Curcumin

100  mg/kg, p.o. 30  min

before PTZ for 40  days

PTZ every other day for

30  days (40  mg/kg, i.p.)

adult male Wistar rats

40  days

restored mitochondrial complexes;

reduced ROS production, lipid

peroxidation, and carbonyl protein

content; restored GSH levels; protected

mitochondria from structural changes

reduced cognitive impairment [107]

Curcumin

150  mg/kg, p.o. 2  weeks

before pilocarpine

Li (127  mg/kg, i.p.) pilocarpine

(30  mg/kg, i.p.) fractionated

adult male

Sprague-Dawley rats

chronic phase

regulated aberrant phosphatase

and tensin homolog (PTEN)

and protein kinase  B (Akt) expression

reduced hippocampal

neurodegeneration;

suppressed seizure development

[108]

Resveratrol

15  mg/kg, p.o.

kainic acid 2.5  μl

(0.4  μg/μl, i.h.

adult male Wistar rats

3, 14, 60 days after seizures

increased kainite receptor subunit

(GluK2) expression and decreased

GABA-A receptor alpha1 expression;

reduced Glu/GABA ratio in hippocampus

antiepileptic effect [109]

Resveratrol

15  mg/kg, p.o. for 10  days

in model animals

PTZ kindling (35  mg/kg, i.p.

28  days)

adult male

Sprague-Dawley rats

after treatment

reduced S100B protein (calcium-

binding protein from S100 family) level

in cerebrospinal fluid (CSF) and serum

restored cognitive function;

reduced neurodegeneration

in hippocampal CA1 and CA3

[110]

NADPH oxidase inhibitors

Apocynin

60  mg/L in drinking water

for 7  days before seizures

(~10.4  mg/kg daily)

pilocarpine (360  mg/kg, i.p.)

adult male Wistar rats

reduced ROS production reduced neurodegeneration [64]

ZAKHAROVA et al.742

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

Table 2 (cont.)

Treatment Seizure induction

Subject

Analysis time

Biochemical effects Functional effects References

Apocynin

30  mg/kg, i.p. 2 and 24  h

after seizures

LiCl (127  mg/kg, i.p.),

pilocarpine (25  mg/kg,

i.p. 19  h later)

adult male

Sprague-Dawley rats

reduced ROS production and lipid

peroxidation

reduced hippocampal

neurodegeneration;

reduced BBB disruption,

neutrophil infiltration,

and microglial activation

[74]

NOS inhibitors

Aminoguanidine

50, 100  mg/kg, i.p. for

15  days with PTZ; 50,

100  mg/kg, i.p. for 30  days

from day  7 after pilocarpine

PTZ kindling (40 mg/kg, i.p.,

15 days);

pilocarpine (100 mg/kg, i.p.,

fractionated)

male Swiss albino mice

not studied suppressed PTZ- and

pilocarpine-induced seizures

[81]

1400W

20  mg/kg, i.p. twice daily

for 3  days

kainic acid

adult male

Sprague-Dawley rats

latent and chronic phases

not studied reduced epileptiform spikes

and SRS; reduced astrogliosis,

microgliosis, serum albumin, and

neurodegeneration in hippocampus,

amygdala, and entorhinal cortex

[82]

Mitochondrial antioxidants

MitoQ pilocarpine

mice

restored CREB, PKA, CaMKIV,

arc and c-fos expression

prevented oxidative neuronal

damage and memory deficit

[111]

AEOL 11207

5  mg/kg, s.c. daily from P5

Sod2

–/–

mice B6D2F2

P14-P21

reduced aconitase inactivation,

3-nitrotyrosine formation, depletion

of reduced coenzyme  A and ATP levels

reduced SRS frequency

and duration;

increased mean lifespan

[112]

Combination therapies with antioxidants

a)  N-acetylcysteine (NAC)

500  mg/kg, i.p. twice daily

for 7  days;

b)  Sulforaphane (SFN)

5  mg/kg, i.p. daily

for 14  days;

c)  NAC+SFN: each alone;

7 days combination  +

7  days SFN

electrically induced status

epilepticus

adult male

SpragueDawley rats

latent and chronic phases

combination reduced oxidative stress

better than either drug alone

combination delayed epilepsy

manifestation, reduced

SRS frequency;

reduced neurodegeneration

and cognitive deficit

[65]

METABOLIC REPROGRAMMING OF GLIA IN EPILEPTOGENESIS 743

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

Table 2 (cont.)

Treatment Seizure induction

Subject

Analysis time

Biochemical effects Functional effects References

a)  AEBSF

50  mg/kg twice;

b)  RTA480 25  mg/kg;

c)  AEBSF+RTA

kainic acid (5  mg/kg)

adult male

Sprague-Dawley rats

chronic phase

not studied suppressed spontaneous seizures

and modified epilepsy severity

[113]

NAC

100 mg/kg, i.p.

Levetiracetam (LEV)

50 mg/kg, i.p.

Gabapentin (GBP)

100 mg/kg, i.p.

NAC+LEV, i.p.

NAC+GBP, i.p.

14  days

traumatic brain injury, then

PTZ (30+15+15  mg/kg 30  min

intervals, i.p.)

not studied 50  mg/kg LEV and 100  mg/kg

GBP reduced seizures;

NAC+GBP combination showed

better seizure control

[114]

Valproate (VPA)

500  mg/kg, p.o.

Astaxanthin (ASTA)

100  mg/kg, p.o.

Combination

with 2  h interval;

all given daily

PTZ (30  mg/kg, i.p.)

3 times weekly

adult male Wistar rats

in combination therapy, ASTA reduced

oxidative stress and TNF content

and increased GSH levels

in combination therapy, ASTA

potentiated the antiepileptic

effect of VPA;

combination also improved

behavioral and histopathological

changes

[89]

VPA

100  mg/kg

Vitamin E

100  mg/kg

Given 30  min after

PTZ (p.o.) once daily

for 10 days and i.p.

every 48 h

(days 1, 3, 5, 7, 9)

PTZ (35 mg/kg, i.p.) every

48 h + cypermethrin

(6.25 mg/kg, p.o.)

reduced neuroinflammation,

MDA levels, and SOD activity

reduced seizure and improved

neuronal integrity

[90]

Note: i.c.v., intracerebroventricularly; s.c., subcutaneously; p.o., orally. i.cort., intracortically.

ZAKHAROVA et al.744

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

Fig.  2. Mechanisms underlying neuroinflammation development in epileptogenesis. Both activated astrocytes and microg-

lia contribute to the development of neuroinflammation, with IL-1β signaling pathway serving as a key regulator of this

process. Seizures induce the efflux of K

and Cl

−

, along with the release of ROS and mitochondrial DNA, leading to the

NLRP3 inflammasome activation. This initiates the autocatalytic activation of caspase-1, which cleaves pro-IL-1β into IL-1β,

triggering a strong proinflammatory response. Concurrently, endogenous anti-inflammatory defense mechanisms are acti-

vated; however, they prove insufficient to suppress the pathological cascade during epileptogenesis, resulting in a vicious

cycle of chronic neuroinflammatory activation and disease progression. Therapeutic strategies involve inhibition of this

pathway using NLRP3 antagonists (CY-09, MCC950), blockade of the IL-1β receptor (anakinra), inhibition of mTOR (rapamy-

cin), and administration of anti-inflammatory cytokines (IL-1RA, IL-10, IL-4), thereby attenuating glial activation and seizure

syndrome.

inhibitors targeting specific pathological sources of

free radicals (NADPH oxidase, iNOS) and regulatory

hubs (HIF-1α) that predominantly modulate induced

rather than basal radical production.

Thus, targeting oxidative stress in epilepsy is a

promising direction (Table  2), but it must go beyond

a simple use of antioxidants. Interventions aimed at

specific sources of ROS (e.g., inhibitors of NADPH

oxidase or iNOS) and key regulatory hubs such as

HIF-1α may not only reduce oxidative damage but

also modulate fundamental mechanisms of epilepto-

genesis and treatment resistance. At the same time,

even targeted inhibition of NADPH oxidase or iNOS

requires caution, as both enzymes contribute to host

defense against pathogens. Furthermore, the effects of

HIF-1α inhibitors, as described above, depend on the

epileptogenesis phase. In this regard, successful clin-

ical translation of these approaches requires careful

estimation of the therapeutic window, development

of isoform-specific inhibitors, and assessment of the

benefit/risk ratio in long-term experimental models.

NEUROINFLAMMATION:

FROM PROTECTION TO CHRONIC

INFLAMMATION

Neuroinflammation is a complex process medi-

ated by various central nervous system (CNS) cells;

it is critically important for protection against in-

fections and injury under normal conditions  [115].

Dysregulation of this protective function and the

development of uncontrolled neuroinflammation are

characteristic of several neurological disorders, in-

cluding epilepsy  [116]. Both astrocytes and microglia

participate in this process and engage in bidirectional

METABOLIC REPROGRAMMING OF GLIA IN EPILEPTOGENESIS 745

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

communication: microglia can induce astrocyte acti-

vation, while astrocytes can initiate activation of mi-

croglia and regulate its cellular function (Fig.  2)  [117].

An important aspect of these interactions is the mutu-

al suppression of excessive microglial and astrocytic

activation through various anti-inflammatory media-

tors [117].

Uncontrolled reactive gliosis can lead to increased

production of proinflammatory factors and impaired

glia-mediated regulation of ions and neurotransmit-

ters. These changes can contribute to the glutamatergic

system, the hyperactivity of which underlies epilepsy

[13,  118]. Both activated astrocytes and microglia con-

tribute to these pathological processes  [119]. A princi-

pal regulator of neuroinflammation is IL-1β signaling,

which triggers a robust proinflammatory response.

Experimental studies demonstrated its early activa-

tion in seizure-related brain regions following status

epilepticus  [120]. NLRP3 (NOD-like receptor family,

pyrin domain containing  3) inflammasome is a key

complex responsible for the production of biologically

active IL-1β  [121]. NLRP3 functions as an intracellular

stress sensor: upon activation, it oligomerizes, binds

to the adaptor protein ASC, and recruits procaspase-1,

forming an active inflammasome  [122]. This leads

to autocatalytic activation of caspase-1, which then

converts pro-IL-1β and pro-IL-18 into their mature,

biologically active forms. NLRP3 activation is trig-

gered by upstream signals, such as K

and Cl

−

efflux,

ROS production, and release of mitochondrial DNA

[123], highlighting the interplay between neuroin-

flammation and oxidative stress. Status epilepticus

has been shown to induce transcription of NLRP3 in-

flammasome components  [124]. Increased expression

of this inflammasome has been observed both in pa-

tients with temporal lobe epilepsy and corresponding

animal models  [125]. Accordingly, modulation of the

NLRP3 inflammasome represents a potential thera-

peutic approach for epilepsy.

In the kindling experimental model, rapamycin,

an mTOR inhibitor, delayed seizure onset and up-

regulated expression of antioxidant enzymes, while

reducing expression of genes encoding IL-1β and

NLRP3  [126]. Similarly, in a kainate induced epilepsy

model, combined treatment with valproic acid and

furosemide reduced protein levels of NLRP3 inflam-

masome components and attenuated seizure severi-

ty  [127]. Direct targeting of the NLRP3 protein by the

compound CY-09 produced a pronounced anti-inflam-

matory effect  [128]. CY-09 slowed the progression of

kindling, inhibited PTZ-induced neuronal loss, and

attenuated astrocyte activation and NLRP3-depen-

dent neuroinflammation  [129]. The potent NLRP3

inhibitor MCC950 suppressed IL-1β pathway signal-

ing  [123] and mitigated neuronal loss following spinal

cord injury  [130], as well as in  vitro under conditions

of increased NLRP3 inflammasome activity  [131].

PTZ-induced neuronal loss was significantly sup-

pressed in NLRP3-deficient mice compared to wild-

type animals  [131], confirming the key role of the

NLRP3 inflammasome in seizure-associated neuro-

nal apoptosis. However, interpretation of these data

should account for a significant heterogeneity of neu-

roinflammatory responses. Indeed, in two classical

models of temporal lobe epilepsy – the pilocarpine

and kainate models – different patterns of NLRP3-

dependent signaling activation have been observed,

raising questions about the reproducibility of inhib-

itor effects across experimental models  [124]. Thus,

the caspase-1 inhibitor CZL80 effectively terminated

kainite-induced status epilepticus, but failed to do so

in the pilocarpine model  [132].

Along increased NLRP3 inflammasome activity,

levels of proinflammatory cytokines such as IL-1β,

TNF, and interleukin-6 (IL-6) have been consistently

reported elevated in patients with epilepsy and in

the brains of experimental animals across various

models of epilepsy or acute status epilepticus  [133].

Glia-derived proinflammatory proteins, in particular

IL-1β and TNF, have been shown to lower the sei-

zure threshold in acute seizure models  [134,  135],

contribute to the development of chronic epileptic

processes in the brain  [136,  137], and promote epi-

lepsy-related behavioral impairments  [138]. Various

anti-inflammatory therapeutic approaches have

demonstrated high efficacy in suppressing sponta-

neous seizures in different experimental models of

both genetic and acquired epilepsy (Table 3) [139].

In particular, blockade of IL-1β receptors led to a

marked reduction in CNS pathomorphological chang-

es in the kainate and lithium–pilocarpine models of

temporal lobe epilepsy  [140]. Experiments conducted

in our laboratory have demonstrated that adminis-

tration of anakinra, a recombinant form of the IL-1β

receptor antagonist, during the latent phase of the

lithium–pilocarpine model significantly reduced the

duration and frequency of SRSs in the chronic phase,

as well as exerted the neuroprotective effect  [136].

Furthermore, anakinra treatment upregulated ex-

pression of the Slc1a2 gene encoding the glutamate

transporter EAAT2, in the rat hippocampus, which

may contribute to the observed neuroprotective ef-

fect of this drug. However, complete blockade of the

IL-1β pathway carries potential risks and represents

a significant limitation, as IL-1β plays an important

physiological role in the CNS immune defense, and

its long-term inhibition may increase susceptibility

to infections, impair tissue remodeling after injury,

and disrupt synaptic homeostasis. Moreover, the ef-

ficacy of IL-1β blockade may be limited by the pres-

ence of compensatory proinflammatory mechanisms

independent of this signaling pathway (e.g., TNF-

ZAKHAROVA et al.746

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

Table 3. Pharmacological modulation of neuroinflammation in models of seizures and epileptogenesis

Treatment Seizure induction

Subject

Analysis time

Biochemical effects Functional effects References

NLRP3 inhibitors

CY-09 PTZ kindling

mice

reduced

NLRP3-dependent

neuroinflammation

slowed kindling

progression, reduced

neuronal loss,

attenuated astrocyte

activation

[129]

CY-09 PTZ kindling

mice

suppressed NLRP3

inflammasome

activation and

neuroinflammation;

inhibition of the

SGLT2/NHE-1/NLRP3

signaling pathway

mitigated oxidative

damage by reducing

ROS production and

lipid peroxidation

while enhancing

antioxidant

defense

reduced seizure

severity,

EEG abnormalities,

and seizure duration;

improved spatial

learning and memory

[149]

siRNA NLRP3 cannula amygdala

kindling-induced

status epilepticus

adult male

Sprague-Dawley rats

reducing NLRP3

levels decreased

IL-1β and IL-18 levels

at 12  h after seizures

suppressed

development and

severity of SRSs

in the chronic phase;

reduced

neurodegeneration

in hippocampal

CA1 and CA3 areas

at 6  weeks after

seizures

[150]

Targeting the IL-1β pathway

Anakinra

100 mg/kg, i.p.

for 5  days after

seizures

50  mg/kg, i.p.

until days  6-10

after seizures

LiCl (127  mg/kg, i.p.)

Pilocarpine

(fractionated

10  mg/kg up to 40  mg/kg

every 30  min, i.p.)

young male

Wistar rats

latent and chronic

phases

increased expression

of the Slc1a2 gene

encoding EAAT2

protein in rat

hippocampus

suppressed duration

and frequency of SRS;

exerted

neuroprotective effect

in rat hippocampus

[136]

Anakinra

100  mg/kg, i.p.

for 5  days after

seizures

50  mg/kg, i.p. until

day  7 after seizures

LiCl (127 mg/kg, i.p.)

Pilocarpine

(fractionated

10  mg/kg

up to 40  mg/kg

every 30  min, i.p.)

young male

Wistar rats

latent phase

reduced Il1b gene

expression; restored

Arg1 gene expression

to control levels

not studied [151]

METABOLIC REPROGRAMMING OF GLIA IN EPILEPTOGENESIS 747

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

Table 3 (cont.)

Treatment Seizure induction

Subject

Analysis time

Biochemical effects Functional effects References

Anakinra

VX-765

Administered

for 5 or 7  days

starting 3  h after

electrical stimulation

or 1  h after seizures

electrical stimulation

adult male

Sprague-Dawley rats

LiCl/pilocarpine

adult female

Sprague-Dawley rats

reduced IL-1β

expression

in astrocytes

reduced cell loss

in rat forebrain

[140]

IL-1RA (interleukin-1

receptor antagonist)

25  mg/kg, i.p.

2  h before electrical

stimulation

electrical stimulation

young male

Wistar rats

2  h before

lipopolysaccharide

(LPS) 50  μg/kg, i.p.

not studied blocked kindling

progression,

restored reduced

after discharge

threshold (ADT)

and after discharge

duration (ADD),

and mitigated

LPS-enhanced

epileptogenesis

[152]

IL-1RA

3.5-35  μg/kg, i.v. 2  h

before scopolamine

and pilocarpine

scopolamine

1  mg/kg

pilocarpine

(320  mg/kg)

adult male

Sprague-Dawley rats

not studied reduced incidence

of status epilepticus

and BBB damage

[153]

VX-765

200  mg/kg, i.p. once

daily for 3  days; on

day  4 given 45  min

before stimulation

electrical stimulation

adult male

Sprague-Dawley rats

prevented increase

in IL-1β levels in

forebrain astrocytes

blocked kindling

development;

seizures could not be

induced in rats for

24  h after kindling

and drug withdrawal

[154]

Cyclooxygenase-2 (COX-2) inhibitors

Rofecoxib

10  mg/kg, i.p. 6-8  h

after seizures twice

daily for 3  days

kainic acid

(10  mg/kg, i.p.)

adult

Sprague-Dawley rats

not studied reduced hippocampal

cell loss

[155]

Parecoxib

10  mg/kg, i.p. 1.5  h

after seizures twice

daily for 18  days

LiCl/pilocarpine

(20-50  mg/kg, i.p.)

female

Sprague-Dawley rats

not studied reduced SRS severity;

exerted

neuroprotection

in hippocampus

and piriform cortex;

caused moderate

reduction in learning

deficits and prevented

motor hyperactivity

[156]

Celecoxib

0.2, 2, 20  mg/kg, p.o.

once 1  h before PTZ

PTZ (60  mg/kg, i.p.)

adult male Wistar rats

not studied 2  mg/kg,

anticonvulsant effect;

0.2 and 20  mg/kg,

no anticonvulsant

effect

[157]

ZAKHAROVA et al.748

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

Table 3 (cont.)

Treatment Seizure induction

Subject

Analysis time

Biochemical effects Functional effects References

Anti-inflammatory cytokines

IL-10

1 and 10  ng/ml

10  min before hypoxia

and throughout the

episode

in vitro

hypoxia-induced

epileptiform activity

adult male Wistar rats

not studied IL-10 (1  ng/ml)

completely

suppressed

development

of epileptiform

activity, whereas

its protective effect

was less pronounced

at 10  ng/ml

[143]

IL-4

100  ng/5  μl i.c.v.

traumatic brain injury;

PTZ kindling

(35  mg/kg, i.p.) every

48  h (3  injections)

adult male Wistar rats

suppressed TNF

expression,

upregulated TGF-β,

IL-10 and ARG1

expression

reduced lesion

volume and number

of damaged neurons;

increased the

number of Iba1/

Arg1-positive cells

[145]

IFN-γ

100  ng/rat, i.p.;

IL-4

100  ng/rat, i.p.;

Administered

for 5 days

pilocarpine

(345  mg/kg, s.c.)

Adult male

C57BL/6J mice

not studied reduced frequency,

duration, and

severity of SRSs;

improved performance

in the Morris

water maze

[158]

Note. i.v., intravenously.

or IL-6-mediated ones), which may sustain neuroin-

flammation and seizure activity even upon complete

suppression of IL-1β.

Interleukin-10 (IL-10) is an anti-inflammatory cy-

tokine that, in combination with transforming growth

factor beta (TGF-β), inhibits several proinflammato-

ry mediators, including IL-1β, TNF, and IL-6  [141].

In the rat model of traumatic brain injury, admin-

istration of exogenous IL-10 reduced CNS levels of

proinflammatory IL-1β and TNF  [142]. In  vitro, ap-

plication of IL-10 to hippocampal slices suppressed

hypoxia-induced epileptiform activity  [143]. IL-10

has also been shown to inhibit IL-1β production and

NLRP3 inflammasome activation in mice following

picrotoxininduced seizures  [144].

Intracerebroventricular administration of anoth-

er anti-inflammatory cytokine, interleukin-4 (IL-4),

exerted neuroprotective effects and suppressed TNF

expression, while increasing TGF-β and IL-10 levels

in rats in the epilepsy model induced by traumatic

brain injury and PTZ administration  [145]. Collective-

ly, these findings suggest that the use of anti-inflam-

matory cytokines may significantly reduce neuroin-

flammation, which in turn may alleviate epilepsy and

potentially slow down epileptogenic processes.

Despite these promising positive effects, the ther-

apeutic potential of anti-inflammatory cytokines re-

mains limited due to the pleiotropic action of these

compounds. For example, along with anti-inflamma-

tory effects, IL-4, modulates synaptic plasticity [146]

and neurogenesis [147]. In addition, delivery remains

a key unresolved issue, as systemic administration of

cytokines is hindered by their inability to effectively

cross the BBB [148], whereas intracerebroventricular

administration, which is commonly used in experi-

mental studies, is difficult to implement in clinical

practice.

It is important to note that the efficacy of anti-in-

flammatory interventions critically depends on the

timing of administration: treatment during the latent

period may produce effects that differ substantially

from those observed in the chronic phase of epi-

lepsy. Furthermore, sex and age also affect the neu-

ro-inflammatory response. Sex-related differences in

cytokine expression, glial activity, and seizure suscep-

tibility may influence sensitivity to anti-inflammato-

ry therapy  [159]. However, the majority of preclinical

studies have been conducted in young male animals,

limiting extrapolation of these findings to the hetero-

geneous population of patients with epilepsy.

METABOLIC REPROGRAMMING OF GLIA IN EPILEPTOGENESIS 749

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

Therefore, neuroinflammation mediated by acti-

vated astrocytes and microglia plays a central role in

epileptogenesis, contributing both to the generation

of seizure activity and to the progression of struc-

tural and functional CNS abnormalities. Experimen-

tal studies have demonstrated that pharmacological

modulation of the IL-1β pathway not only suppress

seizure activity but also exert a neuroprotective ef-

fect, supporting the fundamental possibility of modi-

fying epileptogenesis through intervention at the glial

level. However, critical analysis of data presented

above reveals significant limitations, such as the lack

of reproducibility across models, strong dependence

on the timing of intervention, the absence of clinical

validation for most compounds, and potential risks

associated with long-term immunosuppression. Trans-

lation of these strategies into clinical practice will

require standardization of preclinical study protocols

to include animals of both sexes and different ages,

development of biomarkers to identify patients with

predominant NLRP3/IL-1β-dependent neuroinflamma-

tion, and conduction of well-designed randomized

clinical trials to establish both efficacy and, no less

importantly, long-term safety of therapies targeting

innate immunity pathways in the CNS.

SYSTEMIC METABOLIC REPROGRAMMING

Molecular mechanisms of ketogenic diet: mod-

ulation of neuroinflammation and oxidative stress

in glia in epilepsy. In addition to approaches that se-

lectively target individual glial components, a promis-

ing strategy is systemic metabolic reprogramming of

the brain via dietary interventions. The most exten-

sively studied and clinically significant example is the

ketogenic diet (KD), which has demonstrated efficacy

in refractory and pediatric epilepsy [160-162]. Differ-

ent variants of KD exert a multifactorial, integrated

effect that modulates systemic metabolic parameters:

blood glucose levels and, accordingly, insulin levels

decrease and stabilize, while the concentration of

circulating free polyunsaturated fatty acids increases.

Intensive oxidation of fatty acids leads to the devel-

opment of ketosis, characterized by the appearance in

the blood of ketone bodies such as β-hydroxybutyrate

(BHB) and acetoacetate, which become one of the pri-

mary energy sources for the body’s cells. This process

is accompanied by an overall reduction in caloric in-

take and modulation of the gut microbiota  [163,  164].

The antiepileptic efficacy of KD is likely explained

by the ability of ketone bodies, especially BHB, to

comprehensively modulate epilepsy-associated alter-

ations in astrocytic and microglial metabolism. How-

ever, the strength of evidence supporting individual

links in this chain varies considerably, ranging from

direct experimental findings in epilepsy models to in-

ferences drawn from related research areas such as

neuroinflammation and neurodegeneration.

The most compelling evidence, derived directly

from experimental epilepsy models, pertains to the

restructuring of energy metabolism, which constitutes

the fundamental basis of the diet’s antiseizure action.

For example, KD has been shown to induce coordi-

nated activation of genes involved in mitochondrial

and metabolic pathways in the rat hippocampus, ac-

companied by mitochondrial biogenesis and increase

in energy reserves (e.g., phosphocreatine)  [165]. These

changes may contribute to stabilization of energy ho-

meostasis within the epileptic focus, thereby reducing

neuronal excitability  [166].

In contrast, evidence regarding modulation of

glial inflammatory responses is more heterogeneous,

combining the data obtained directly in epilepsy mod-

els and insights from extrapolated from neurodegen-

erative disease studies. It has been hypothesized that

BHB can interrupt the vicious cycle of neuroinflam-

mation that sustains hyperexcitability of neuronal

networks, by modulating proinflammatory pathways

in microglia. In particular, BHB inhibits activation

of the NLRP3 inflammasome in  vitro, a key initiator

of the inflammatory cascade in microglia and mac-

rophages  [167]. In models of multiple sclerosis and

Alzheimer’s disease, KD suppressed the proinflam-

matory TLR4/MyD88/NF-κB/NLRP3 and JAK1/STAT1

pathways, resulting in reduced expression of cyto-

kines (TNF, IL-6), a shift toward an anti-inflammatory

microglial phenotype, and reduction of microgliosis

[168-171]. It is assumed that similar mechanisms also

operate during epileptogenesis, which has been sup-

ported by a number of indirect findings. Thus, direct

administration of BHB to rats with kainate-induced

epilepsy led to a decrease in the astroglial marker

GFAP  [172]. In mice with a genetic model of epilepsy,

KD increased expression of PPARγ2 (peroxisome pro-

liferator-activated receptor gamma  2), which regulates

genes involved in anti-inflammatory and antioxidant

pathways, also indicating modulation of neuroinflam-

mation  [173]. In addition, in the kainate model of ep-

ilepsy, KD prevented upregulation of phosphorylated

S6 protein  (pS6), a key marker of mTOR activation

[174]. Nevertheless, the precise contribution of spe-

cific mechanisms of microglial reprogramming under

KD in epilepsy requires further investigation.

Suppression of oxidative stress is widely consid-

ered a key component of the mechanism of action of

KD. In the rat hippocampus, KD activates Nrf2 (nucle-

ar factor erythroid  2-related factor  2), which regulates

expression of genes mediating antioxidant defense

in glial cells  [175], and increases glutathione perox-

idase (GPX) activity  [176]. This is consistent with the

reports on increased levels of the antioxidant GSH

ZAKHAROVA et al.750

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

under conditions of elevated BHB and KD in epilepsy

models, suggesting improved redox status and mito-

chondrial protection  [172,  177]. However, it remains

unresolved whether these effect arise directly from

ketone metabolism in glial cells or result from the

overall stabilization of neuronal activity.

The most direct evidence for KD-induced repro-

gramming of astrocyte metabolism comes from its

effect on the adenosinergic system, a key endoge-

nous component of the anticonvulsant pathway. In

a genetic mouse model of epilepsy, KD suppressed

seizures by activating adenosine A1 receptors  [178].

This effect is linked to a downregulation of adenos-

ine kinase (ADK), the principal enzyme of adenosine

metabolism in astrocytes. The significance of this

mechanism is supported by observations of increased

ADK expression in the hippocampus of patients with

pharmacoresistant epilepsy [179].

Further support for KD-associated anticonvulsant

mechanisms is provided by the antiseizure action of

ketone bodies themselves, which has been demon-

strated in several genetic models of epilepsy  [173,

180,  181].

Therefore, the therapeutic action of KD can be ex-

plained by a combination of interrelated mechanisms

with varying degrees of evidentiary support. Well-es-

tablished effects include enhancement of brain energy

metabolism and metabolic reprogramming of astro-

cytes. Another promising effect that requires further

verification in epilepsy models is the modulation of

neuroinflammation and oxidative stress in glial cells.

Despite proven efficacy, the use of KD is limited due

to contraindications in some patients, poor dietary

adherence, and adverse side effects such as gastro-

intestinal disturbances and metabolic disorders  [162].

These limitations have driven ongoing efforts to im-

prove tolerability and accessibility, including the de-

velopment of more flexible dietary protocols (e.g.,

modified Atkins diet), the use of exogenous ketone

supplements, and combination with conventional an-

tiepileptic drugs to enhance the therapeutic effect.

PPAR agonists as a tool for targeted metabol-

ic reprogramming of glia during epileptogenesis.

Activation of peroxisome proliferator-activated recep-

tors (PPARs) is one of the key mechanisms underlying

the neuroprotective effects of KD  [173]. The use of

PPAR agonists in epilepsy therapy has been actively

discussed in recent years  [182-184]. In this context,

PPARs are viewed as promising therapeutic targets

for correcting disrupted metabolism in astrocytes and

microglia during epileptogenesis.

The PPARs family comprises nuclear transcription

factors that regulate the expression of genes involved

in core physiological processes such as carbohydrate

and lipid metabolism, inflammatory responses, cellu-

lar differentiation, and apoptosis  [185]. The family in-

cludes three isotypes – PPARα, PPARβ/δ, and PPARγ –

which differ in tissue distribution, ligand specificity,

and functional roles  [185]. PPARs are expressed in

neurons, oligodendrocytes, microglia, and astrocytes

[186,  187]. Their presence in astrocytes and microglia

underlies their capacity to serve as key regulators

and targets for metabolic reprogramming of the glial

network under pathological conditions.

The effects of PPAR agonists in different epilep-

sy models have been attracting increasing attention;

among these compounds, PPARγ agonists are the most

extensively studied. Pioglitazone (PPARγ agonist) has

demonstrated anticonvulsant effects in a PTZ-induced

seizure model  [188]. Another PPARγ agonist, rosigli-

tazone, was found to prevent hippocampal neuronal

loss and the development of SRSs in the lithium–

pilocarpine model of temporal lobe epilepsy  [189,

190]. At the same time, rosiglitazone reduced the

number of GFAP-positive cells (a marker of astro-

gliosis) and decreased the number of IBA1-positive

microglial cells in the hippocampus, indicating direct

inhibition of reactive gliosis  [190,  191]. According to

the results of our studies on the protective effects of

PPARα and PPARβ/δ agonists during epileptogenesis,

the PPARβ/δ agonist cardarine  [192] and the PPARα

agonist fenofibrate  [193] attenuated behavioral distur-

bances characteristic of temporal lobe epilepsy. PPAR

activation is not only involved in mechanisms medi-

ating therapeutic effects of KD, it might also contrib-

ute to the beneficial impact of certain probiotics on

epileptogenesis, as reported by our group and other

authors  [194,  195].

The accumulated evidence supports the use of

PPAR agonists as tools for targeted metabolic repro-

gramming of glia. Their antiepileptogenic effects may

be mediated by receptors expressed on astrocytes

and microglial cells through several mechanisms,

the most prominent of which involves the regulation

of energy metabolism and lipid homeostasis in glial

cells  [22]. As discussed above, epileptic brain is char-

acterized by profound disruptions of energy homeo-

stasis. During an epileptic seizure, energy demand

rises sharply, and astrocyte-derived lactate becomes

an important energy source for neurons. According-

ly, in temporal lobe epilepsy, glucose uptake and me-

tabolism increase during seizures, whereas interictal

periods are characterized by hypometabolism  [196].

PPARγ agonists modulate glucose utilization and lac-

tate production in astrocytes  [197], and PPARα reg-

ulates mitochondrial fatty acid β-oxidation, thereby

enhancing ATP synthesis  [198].

A major consequence of impaired energy me-

tabolism and mitochondrial dysfunction in astrocytes

and microglia during epileptogenesis is the emer-

gence of a pathological metabolic state, in which

glial cells lose their neuron-supporting functions

METABOLIC REPROGRAMMING OF GLIA IN EPILEPTOGENESIS 751

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

and become sources of ROS and proinflammatory

signals  [22,  199]. PPAR agonists counteract this phe-

notypic shift by simultaneously restoring energy

balance and suppressing oxidative stress and neu-

roinflammation  [60,  117]. In the lithium–pilocarpine

model, the PPARγ agonist rosiglitazone reduced ROS

generation and lipid peroxidation, increased SOD ac-

tivity and GSH levels, and decreased HO-1 expression,

these effects being accompanied by reduced neuronal

death in the hippocampus  [200].

The ability to restrain neuroinflammation has

been demonstrated for all PPAR types  [201-203]. PPARα

and PPARγ suppress the production of proinflamma-

tory cytokines in microglial  [204] and astrocytic  [205]

cells. Moreover, the PPARγ agonist pioglitazone has

been shown to influence microglial polarization by

decreasing the expression of M1  markers and increas-

ing the expression of M2  markers  [206-208]. These ef-

fects may be mediated, at least in part, through in-

hibition of the proinflammatory transcription factors

NF-κB and AP-1  [209-211], whereas PPARα directly

upregulates expression of the anti-inflammatory cy-

tokine IL-1RA  [212].

It should be emphasized that many above-de-

scribed mechanisms of PPAR agonist action have

been demonstrated in non-epileptic models. Although

existing evidence strongly suggests that PPARs me-

diate glial reprogramming in epilepsy through these

pathways, definitive confirmation will require studies

specifically designed to investigate these mechanisms

in astrocytes and microglia during epileptogenesis.

The above-described properties of PPAR agonists

are also indirectly manifested in experimental models

of epilepsy. In particular, the PPARγ agonist rosiglita-

zone reduced CD40 expression in activated microglia

and suppressed TNF production in the hippocampus.

These effects were abolished by the selective PPARγ

antagonist T0070907, supporting a PPARγ-dependent

mechanism  [190]. Our studies in the same epilepsy

model showed that the PPARβ/δ agonist GW0742 at-

tenuated the epileptogenesis-induced upregulation of

genes encoding the activated microglia marker (Aif1/

IBA1), as well as Nlrp3 and Il1rn genes, in the cortex

[213], suggesting an effect on NLRP3-dependent neu-

roinflammation in glial cells. We also demonstrated

that the PPARα agonist fenofibrate reduced the ele-

vated expression of Aif1 and Nlrp3 in the temporal

cortex  [193]. Both compounds also affected the pro-

duction of the markers of proinflammatory  (Lcn2)

and neuroprotective (Ptx3, Arg1) glial phenotypes,

pointing to an ability to shift glial cells from one phe-

notype to another  [193,  213].

Despite compelling preclinical evidence, the clin-

ical use of PPAR agonists remains limited by adverse

effects and low BBB permeability. Promising direc-

tions include the development of selective receptor

modulators with improved safety profiles, the design

of formulations and carriers for targeted delivery to

the brain, and the search for strategies enabling se-

lective activation of PPARs in glial cells.

Overall, pharmacological activation of PPARs

represents a promising strategy for correcting met-

abolic and inflammatory disturbances in the glial

network during epileptogenesis. The data presented

in this section indicate that PPAR agonists can shift

astrocytes and microglia from proinflammatory to

neuroprotective phenotypes. However, it is important

to emphasize that many of the proposed molecular

mechanisms have been validated primarily in other

neuropathology models and require direct experimen-

tal proof in epilepsy-specific settings. Nevertheless,

the accumulated evidence supports PPAR agonists as

an attractive tool for targeted metabolic reprogram-

ming of glia, although their clinical translation will

require addressing selectivity, delivery across the

BBB, and thorough evaluation of long-term safety.

Multitarget effects of GLP-1 receptor agonists

in the context of epileptogenesis. Glucagon-like pep-

tide-1 (GLP-1) receptor agonists are a class of drugs

originally developed for the treatment of type  2 di-

abetes mellitus  [214]. Their mechanism of action is

based on mimicking the biological activity of the

endogenous hormone incretin. Activation of GLP-1

receptors in tissues not typically associated with dia-

betes mediates neuroprotective, cardioprotective, and

nephroprotective effects, opening up possibilities for

repurposing these drugs  [215]. Depending on their

molecular structure, GLP-1 receptor agonists are di-

vided into two main groups: human GLP-1 analogs

(e.g., liraglutide, semaglutide, dulaglutide) and exen-

din-4 derivatives (exenatide and lixisenatide)  [216].

Their development has been primarily aimed at over-

coming an extremely short half-life of native GLP-1

(1-2  min), which is due to rapid degradation by di-

peptidyl peptidase-4 and accelerated renal clearance.

Regardless of structural differences, all GLP-1 ag-

onists act through the same Gs  protein-coupled recep-

tor  [217]. Activation of this receptor triggers a canoni-

cal intracellular signaling cascade including adenylate

cyclase stimulation, increase in cyclic AMP (cAMP)

concentration, and subsequent activation of protein

kinase  A  (PKA). In pancreatic β-cells, this pathway me-

diates insulin secretion in a strictly glucose-dependent

manner. However, GLP-1 receptors are also widely ex-

pressed in other organs and systems, in particular,

the CNS, cardiovascular system, and kidneys  [218].

Of particular relevance to epileptogenesis is the

ability of GLP-1 agonists to correct the imbalance

between excitatory and inhibitory transmission at

synapses, a key pathophysiological link in epilepsy.

Wen et  al.  [219] used the PTZ kindling model to

demonstrate that liraglutide induced a coordinated

ZAKHAROVA et al.752

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

remodeling of the hippocampal receptor profile.

Liraglutide reduced the expression of ionotropic glu-

tamate receptor subunits (GluA1–4, GluN1, GluN2A/B),

which are responsible for excitation, while simultane-

ously increasing the level of the GABAARβ2/3 subunit,

which is necessary for inhibitory transmission  [219].

The anti-inflammatory effect of GLP-1 agonists

is exerted at multiple levels of the inflammatory re-

sponse regulation, in which the transcription factor

NF-κB plays a central role. NF-κB has a dual func-

tion by triggering both proinflammatory  [220] and

anti-inflammatory programs  [221], which explains

the multifaceted context-dependent action of GLP-1

agonists. Rather than causing non-selective suppres-

sion of NF-κB, which could disrupt cellular homeo-

stasis, GLP-1 agonists ensure selective modulation of

this transcription factor via the cAMP/PKA signaling

pathway  [222]. Consequently, expression of the most

pathogenic proinflammatory cytokines, including TNF,

IL-1β, and IL-6, is reduced, whereas the anti-inflam-

matory components of the NF-κB-dependent response,

for example those associated with IL-10, remain in-

tact or are even enhanced, resulting in a functional

reprogramming of inflammation toward a less aggres-

sive phenotype rather than inhibition.

At the effector level, GLP-1 agonists inhibit NLRP3

inflammasome activity  [125]. According to Wang

et al. [223], administration of semaglutide in the PTZ

kindling model significantly reduced both mRNA and

protein levels of NLRP3, which was accompanied by

a decrease in the content of mature forms of IL-1β

and IL-18. Hence, GLP-1 agonists act on the inflam-

masome already at the stage of expression of its key

components, thereby limiting the production of the

most potent proinflammatory mediators.

Of particular importance is the ability of GLP-1

agonists to modulate the microglial phenotype. Wang

et al.  [224] demonstrated that semaglutide promoted

the transition of microglia from the proinflammatory

to the anti-inflammatory state: it increased the ex-

pression of M2 markers (Arg1, YM1) and downregu-

lated M1 markers (CD86, iNOS). This phenotypic shift

interrupts the vicious cycles of chronic inflammation

in the CNS.

Another fundamental neuroprotective mecha-

nism is the attenuation of oxidative stress. GLP-1

agonists activate endogenous antioxidant systems,

primarily through cAMP/PKA-dependent stimulation

of the transcription factor Nrf2. This leads to in-

creased expression of antioxidant enzymes such as

HO-1, SOD, CAT, and GPX  [225]. Simultaneously, mi-

tochondrial homeostasis is improved, likely through

activation of PGC-1α (peroxisome proliferator-acti-

vated receptor gamma coactivator 1-alpha), a master

regulator of mitochondrial biogenesis and oxidative

metabolism  [226]. As a result, the efficiency of oxida-

tive phosphorylation is enhanced, the mitochondrial

membrane potential is stabilized, and cytochrome c

release is blocked, thereby preventing the initiation

of the mitochondrial apoptotic pathway. Experimen-

tal data confirm these effects by demonstrating that

therapy with GLP-1 agonists in epilepsy models leads

to reduced levels of oxidative damage markers (e.g.,

MDA) and increased activity of antioxidant enzymes

in the hippocampus  [227,  228].

MODERN STRATEGIES FOR CORRECTING

EPILEPTOGENESIS: PHARMACOLOGICAL

MODULATION OF METABOLIC SENSORS

AND SELECTIVE TARGETING OF GLIA

USING NANO- AND RNA-BASED THERAPIES

Because the key metabolic pathways (glycolysis,

mTOR/AMPK signaling, oxidative phosphorylation) are

conserved across cell types, their systemic modulation

carries a risk of adverse effects. Therefore, correction

of metabolic reprogramming in reactive glia requires

targeted delivery that can rectify local disturbances

without perturbing peripheral homeostasis.

One of the most promising approaches is tar-

geting of metabolic sensors, core regulatory proteins

that detect and integrate energetic, metabolic, and

oxygenation states of the cell. Central among them is

the AMPK/mTOR axis, i.e., a pair of out-of-phase ki-

nases: a shift toward mTOR hyperactivation promotes

gliosis and chronic neuroinflammation. Increasing ev-

idence demonstrates that this axis can be pharmaco-

logically steered to reprogram the glia. For example,

the N-terminal peptide (Ac2-26) of annexin  A1 acti-

vates AMPK and inhibits mTOR in microglia via the

FPR2/ALX receptor, promoting a transition toward

the anti-inflammatory M2 phenotype and improving

the outcomes, while reducing the BBB damage in the

ischemia–reperfusion model  [229]. Importantly, in

reactive astrocytes, mTOR-dependent modulation of

autophagy regulates secretion of the LCN2 protein,

a marker of the neurotoxic astroglial phenotype,

and increases neuronal survival under inflammatory

stress  [230]. Astrocytes subjected to ischemic stress

transmit metabolic signals to neurons through nico-

tinamide phosphoribosyltransferase (Nampt)-enriched

exosomes, thus activating AMPK, inhibiting mTOR,

inducing autophagy, and exerting neuroprotective

effects [231].

These mechanisms represent attractive targets

for pharmacological intervention. Among available

compounds, the AMPK activator metformin remains

the most extensively studied tool for indirect mod-

ulation of the AMPK/mTOR axis, consistent with its

broad anti-epileptogenic and neuroprotective profile.

In a pilocarpine model of temporal lobe epilepsy,

METABOLIC REPROGRAMMING OF GLIA IN EPILEPTOGENESIS 753

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

metformin suppressed aberrant BDNF–TrkB signal-

ing, delayed seizure progression, and reduced mTOR

activation  [232]. In a lithium–pilocarpine model of

status epilepticus, metformin attenuated microglial

and astroglial activation, suppressed the expression

of proinflammatory mediators (IL-1β, COX-2) and

NF-κB activity, and restored impaired hippocam-

pus-dependent memory  [233]. Prolonged treatment

with metformin reduced the duration of SRSs in a

chronic kainate model and decreased mortality in

the acute PTZ-induced model  [234]. Notably, in the

PTZ paradigm, the anticonvulsant and neuroprotec-

tive effects of this compound were accompanied by

downregulation of NOS isoforms (nNOS, iNOS, eNOS)

and decreased NO levels. Moreover, molecular dock-

ing analysis suggested potential direct interactions

between metformin and these enzymes  [235].

Direct targeting of mTOR has received clinical

validation. The mTOR inhibitors rapamycin (sirolimus)

and everolimus are approved therapies for tuberous

sclerosis and have demonstrated efficacy in reduc-

ing both seizure frequency and tumor volume  [236].

However, emerging evidence indicates that under cer-

tain conditions, mTOR activity may be required for

neuroprotection. In particular, the ABCG2 transporter

was found to provide protection during epileptogen-

esis through functional interaction with the mTOR

pathway, as disruption of this process via ABCG2

knockout worsened the outcomes and increased sei-

zure susceptibility  [237]. Furthermore, accumulating

data suggest that mTOR activation during epileptogen-

esis may represent a consequence of earlier upstream

disturbances, such as dysregulation of Wnt signaling

and associated metabolic reprogramming, rather than

a primary initiating event, as was shown in the ka-

inate and pilocarpine models  [29]. Collectively, these

findings support a shift from indiscriminate mTOR

suppression toward strategies that restore physiolog-

ical pathway dynamics or enable cell type-specific

modulation within specific cell populations.

Achieving such selectivity requires post-transcrip-

tional regulatory tools capable of precisely modulat-

ing gene expression directly in reactive glia. Because

metabolic shifts and neuroinflammation in reactive

glia are governed by common mechanisms, RNA-

based therapy may be used for targeted correction

of these dysregulated processes. A key post-tran-

scriptional regulator of neuroinflammation in glia is

miR-146a. Suppression of its expression in a rat model

of temporal lobe epilepsy not only reduced the levels

of proinflammatory cytokines (IL-1β, IL-6, IL-18) and

GFAP expression, but also exerted a neuroprotective

effect via inhibition of the Notch-1 signaling pathway

[238,  239]. More intricate regulatory networks involve

noncoding RNAs. For instance, circRNA Hivep2 func-

tions as a competing endogenous RNA (ceRNA) for

miR-181a-5p and suppresses microglial activation,

while lncRNA H19 promotes activation of hippocam-

pal glial cells via the Stat3 pathway  [240,  241].

Efficient siRNA-mediated suppression of glia-spe-

cific mRNAs also supports the feasibility of RNA-me-

diated glial targeting. In a pilocarpine model of

temporal lobe epilepsy, siRNA-mediated knockdown

of the proinflammatory P2X7 receptor in microglia

prolonged the latent period and reduced both the

frequency and severity of SRSs  [242]. Similarly, in

a kainate-induced status epilepticus model, siRNA

against thrombospondin-1 (TSP-1), a key activator of

the TGF-β pathway in astrocytes, effectively attenu-

ated the severity of acute seizures and suppressed

astrogliosis  [243,  244].

Implementation of targeted correction of gli-

al metabolism requires delivery systems capable of

crossing the BBB and providing selective uptake by

target cells. Nanoscale carriers and biomimetic ap-

proaches enable local enrichment of therapeutic

agents in regions of metabolic dysfunction, thus re-

ducing the risk of systemic effects. For example, bio-

mimetic macrophage membrane-coated nanoparticles

(MA@RT-HMSNs) selectively accumulate at sites of

neuroinflammation and enable efficient BBB pene-

tration and delivery of the death-associated protein

kinase  1 inhibitor TC-DAPK6, thus demonstrating an-

ticonvulsant, neuroprotective, and anti-inflammatory

effects in an epilepsy model  [245]. For selective cor-

rection of microglial metabolism, PB@ZIF nanoparti-

cles have been developed to reduce ROS levels and

suppresses HIF-1α-dependent reprogramming, thereby

alleviating the course of spontaneous seizures  [246].

The convergence of RNA therapy and nanotechnology

is exemplified by the use of exosomes to protect and

deliver therapeutic nucleic acids, such as the circRNA

Hivep2  [240].

In experimental studies, selenium nanoparticles

(SeNPs) have been proven as promising platforms

due to intrinsic neuroprotective activity and ability to

mitigate pathogenic alterations induced by PTZ  [247].

Prodigiosin-loaded SeNPs reduced seizure severity

and duration, while concurrently suppressing oxida-

tive stress through activation of the Nrf2/antioxidant

system, reduced neuroinflammation by downregulat-

ing IL-1β, TNF, and NF-κB), and inhibited apoptosis

through modulation of Bax/Bcl-2 in the PTZ model

[248]. Rutin-loaded SeNPs restored the neurotransmit-

ter balance and regulated proinflammatory cytokines

(TNF, IL-6) via the Nrf2/HO-1 pathway  [249].

Another promising approach is the use of poly-

meric and lipid nanocarriers that can address the

low bioavailability of many natural compounds.

Thus, ellagic acid encapsulated in calcium alginate

nanoparticles and a nanoformulation of berberine

demonstrated superior anticonvulsant, antioxidant,

ZAKHAROVA et al.754

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

Fig. 3. Astrocyte and microglial remodeling in epileptogenesis and associated pathogenic interactions. Metabolic reprogram-

ming of astrocytes and microglia represents a key integrative pathogenetic link in epileptogenesis. The central process is

energy metabolism shift toward glycolysis under normoxic conditions mediated by the activation of the Wnt/GSK3β and

mTOR signaling cascades. This glycolytic switch accompanied by the decreased TCA cycle activity, leads to the accumulation

of lactate and succinate, promoting stabilization of HIF-1α. Stabilized HIF-1α triggers the expression of proinflammatory

proteins, resulting in the intensification of free radical processes and oxidative stress and establishment of a positive

feedback loop associated with a widespread activation of proinflammatory signaling in tissues and further stabilization of

HIF-1α. In turn, this promotes further metabolic shift toward glycolysis and exacerbates the pathology. Collectively, these

mutually reinforcing processes result in the disruption of the glutamatergic system and ion homeostasis, leading to the

development and exacerbation of neuronal hyperactivity. In the diagram, upward red arrows indicate increases in concen-

tration, expression, or activity; downward red arrows indicate decreased levels or activity.

and anti-inflammatory effects compared with their

free forms in a PTZ model of epilepsy  [250,  251].

Likewise, crocin delivered using solid lipid nanocarri-

ers (SLNCs) ameliorated epilepsy-associated cognitive

deficits, an effect that correlated with reduced neu-

roinflammation (NF-κB)  [252].

Integrating molecular biology approaches, gene

regulation, and nanoengineering provides a strong

foundation for developing targeted therapeutic strat-

egies designed to overcome the limitations of system-

ic metabolic modulation. However, several challeng-

es remain, including ensuring cell-type specificity of

interventions, creating combination platforms (e.g.,

nanoparticles that deliver siRNA), and engineering

“smart” carriers capable of releasing their cargo in

response to biochemical markers of reactive glia.

Although these strategies have shown promise in ex-

perimental models by modulating core mechanisms of

epileptogenesis, their clinical translation will require

confirmation of long-term safety, delivery specificity,

and efficacy in chronic disease settings. Looking

ahead, these approaches may contribute not only to

seizure control but also to the development of truly

anti-epileptogenic interventions aimed at preventing

the onset of epilepsy.

CONCLUSION

Metabolic reprogramming of astrocytes and mi-

croglia represents a key integrative pathogenetic

mechanism in epileptogenesis, linking disturbances

in energy homeostasis, neuroinflammation, oxidative

stress, and neuronal network hyperexcitability in a

self-sustaining pathological loop (Fig.  3). A central

process is the energy metabolism shift toward glycoly-

sis despite adequate oxygen availability (Warburg-like

effect), mediated by activation of the Wnt/GSK3β

and mTOR signaling cascades. Notably, this phe-

nomenon has been observed across various models

METABOLIC REPROGRAMMING OF GLIA IN EPILEPTOGENESIS 755

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

of epileptogenesis, and inhibition of glycolytic en-

zymes has been shown to directly suppress proin-

flammatory activation of microglia. According to a

large body of evidence, the Warburg-like metabolic

shift in glial cells initiates a pathophysiological cycle,

in which enhanced glycolysis coupled with reduced

TCA cycle activity promotes accumulation of lactate

and succinate, leading to stabilization of the tran-

scription factor HIF-1α. Stabilized HIF-1α triggers the

expression of a wide range of genes encoding proin-

flammatory proteins, resulting in intensification of

free-radical processes and oxidative stress. This, in

turn, establishes a positive feedback loop, in which

activation of pro-inflammatory signaling cascades in

tissues- and further stabilization of HIF-1α lead to a

further shift toward the glycolytic phenotype, exac-

erbating the pathology. These mutually reinforcing

processes disrupt glutamate homeostasis and ionic

balance, ultimately inducing and amplifying neuronal

hyperexcitability.

In this context, therapeutic interventions aimed

at correcting these interconnected pathways hold

significant promise. Modulation of individual tar-

gets (mTOR, HIF-1α), as well as systemic approaches

(KD, PPAR agonists, GLP-1 receptor agonists) that af-

fect these targets and processes they regulate, have

demonstrated anti-epileptogenic and neuroprotec-

tive potential in experimental studies. However, the

greatest therapeutic efficacy is likely to be achieved

through combination approaches that simultaneously

target multiple components of the pathological net-

work.

The translation from experimental models to

clinical practice faces several limitations. First, the

temporal dynamics of metabolic changes in glial

cells at different phases of epileptogenesis remain

insufficiently characterized. It is critically important

to define precise therapeutic windows for targeting

metabolic pathways, given the context-dependent role

of certain regulators. For example, HIF-1α may exert

adaptive functions during the acute phase but con-

tribute to pathological remodeling in chronic epilepsy

Second, because glycolysis and oxidative phosphory-

lation are universal metabolic pathways, targeting

them requires the development of cell-specific ap-

proaches and strategies allowing to bypass the BBB

to minimize systemic adverse side effects. In this

context, targeted nanodelivery and RNA therapy hold

significant promise. The creation of biomimetic nano-

systems capable of crossing the BBB and selectively

accumulating in reactive glia opens up possibilities

for targeted correction of pathological metabolic

pathways while limiting systemic exposure. Particu-

larly important is identification of biomarkers of glial

metabolic status (e.g., lactate levels and expression of

glycolytic enzymes in cerebrospinal fluid) to enable

the development of personalized therapies and eluci-

dation of therapeutic windows for intervention. From

a fundamental perspective, future advancements in

cell-specific intervention require an integrative re-

search strategy that will combine the knowledge of

the diversity of functional states of glial cells in vivo

with detailed analysis of accompanying metabolic

rearrangements during epileptogenesis, since most

current studies are focused on metabolism without

taking into account the cell specificity.

Metabolic reprogramming of glial cells opens

new prospects for developing anti-epileptogenic ther-

apy. Successful clinical translation of these strategies

requires interdisciplinary integration of metabolom-

ics, neuroimmunology, and nanomedicine approaches,

enabling the creation of therapies that will not only

control seizures but also modify epilepsy progression

through the restoration of glial homeostasis.

Abbreviations

2-DG 2-deoxyglucose

2-DG6P 2-deoxyglucose-6-phosphate

ADK adenosine kinase

AMPK AMP-activated protein kinase

ARG1

(Arg1 gene)

arginase-1

ASTA astaxanthin

BBB blood-brain barrier

BHB β-hydroxybutyrate

CNS central nervous system

EAAT2

(Slc1a2 gene)

excitatory amino acid transporter  2

GFAP glial fibrillary acidic protein

GLP-1 glucagon-like peptide-1

GSH glutathione

GSK3β glycogen synthase kinase  3β

HIF-1α hypoxia-inducible factor  1α

HK2 hexokinase  2

HO-1 heme oxygenase-1

IL interleukin

IL-1RA interleukin-1 receptor antagonist

KD ketogenic diet

LDHA lactate dehydrogenase  A

MDA malondialdehyde

NAC N-acetylcysteine

NLRP3 Nod-like receptor family pyrin domain

containing  33

PKA protein kinase  A

PKM2 pyruvate kinase  M2

PPAR peroxisome proliferator-activated

receptor

PTZ pentylenetetrazole

RNS reactive nitrogen species

ROS reactive oxygen species

SFN sulforaphane

SOD superoxide dismutase

ZAKHAROVA et al.756

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

SRS spontaneous recurrent seizures

TCA tricarboxylic acid

TGF-β transforming growth factor-β

TNF tumor necrosis factor

TSC2 tuberous sclerosis complex  2

Contributions

M.V.Z., A.A.K., Yu.A.G.; A.P.Sch., O.E.Z., and A.R.Kh.

wrote the text of the article; G.P.D. prepared the fig-

ures; M.V.Z., A.A.K.; G.P.D., and A.V.Z. edited the man-

uscript.

Funding

This work was supported by the Russian Science

Foundation (project no. 25-75-10123).

Ethics approval and consent to participate

This work does not contain any studies involving

human or animal subjects.

Conflict of interest

The authors of this work declare that they have no

conflicts of interest.

REFERENCES

1. Li, W., Wu, J., Zeng, Y., and Zheng, W. (2023) Neuroinflammation in epileptogenesis: from pathophysiology to

therapeutic strategies, Front. Immunol., 14, 1269241, https://doi.org/10.3389/fimmu.2023.1269241.

2. Goldberg, E. M., and Coulter, D. A. (2013) Mechanisms of epileptogenesis: a convergence on neural circuit dys-

function, Nat. Rev. Neurosci., 14, 337-349, https://doi.org/10.1038/nrn3482.

3. Ravizza, T., Scheper, M., Di Sapia, R., Gorter, J., Aronica, E., and Vezzani, A. (2024) mTOR and neuroinflamma-

tion in epilepsy: implications for disease progression and treatment, Nat. Rev. Neurosci., 25, 334-350, https://

doi.org/10.1038/s41583-024-00805-1.

4. Lukasiuk, K. (2014) Epileptogenesis, in Encyclopedia of the Neurological Sciences, vol. 2, Elsevier, pp. 196-199,

https://doi.org/10.1016/B978-0-12-385157-4.00297-9.

5. Lasoń, W., Chlebicka, M., and Rejdak, K. (2013) Research advances in basic mechanisms of seizures and antie-

pileptic drug action, Pharmacol. Rep., 65, 787-801, https://doi.org/10.1016/S1734-1140(13)71060-0.

6. Staley, K. (2015) Molecular mechanisms of epilepsy, Nat. Neurosci., 18, 367-372, https://doi.org/10.1038/nn.3947.

7. Costa, B., and Vale, N. (2023) Understanding Lamotrigine’s role in the CNS and possible future evolution, Int. J.

Mol. Sci., 24, 6050, https://doi.org/10.3390/ijms24076050.

8. Schmidt, D., and Schachter, S. C. (2014) Drug treatment of epilepsy in adults, BMJ, 348, 365-372, https://

doi.org/10.1136/bmj.g254.

9. Löscher, W., and Klein, P. (2021) The Pharmacology and clinical efficacy of antiseizure medications: from bro-

mide salts to cenobamate and beyond, CNS Drugs, 35, 935-963, https://doi.org/10.1007/s40263-021-00827-8.

10. Walia, K. S., Khan, E. A., Ko, D. H., Raza, S. S., and Khan, Y. N. (2004) Side effects of antiepileptics – a review,

Pain Pract., 4, 194-203, https://doi.org/10.1111/j.1533-2500.2004.04304.x.

11. Hiragi, T., Ikegaya, Y., and Koyama, R. (2018) Microglia after seizures and in epilepsy, Cells, 7, 26, https://

doi.org/10.3390/cells7040026.

12. Sanz, P., and Garcia-Gimeno, M. A. (2020) Reactive glia inflammatory signaling pathways and epilepsy, Int. J.

Mol. Sci., 21, 4096, https://doi.org/10.3390/ijms21114096.

13. Devinsky, O., Vezzani, A., Najjar, S., De Lanerolle, N. C., and Rogawski, M. A. (2013) Glia and epilepsy: excitability

and inflammation, Trends Neurosci., 36, 174-184, https://doi.org/10.1016/j.tins.2012.11.008.

14. Yu, C., Deng, X. ju., and Xu, D. (2023) Microglia in epilepsy, Neurobiol. Dis., 185, 106249, https://doi.org/10.1016/

j.nbd.2023.106249.

15. Fan, Y.-Y., and Huo, J. (2021) A1/A2 astrocytes in central nervous system injuries and diseases: angels or devils?

Neurochem. Int., 148, 105080, https://doi.org/10.1016/j.neuint.2021.105080.

16. Therajaran, P., Hamilton, J. A., O’Brien, T. J., Jones, N. C., and Ali, I. (2020) Microglial polarization in posttrau-

matic epilepsy: potential mechanism and treatment opportunity, Epilepsia, 61, 203-215, https://doi.org/10.1111/

epi.16424.

17. Paolicelli, R. C., Sierra, A., Stevens, B., Tremblay, M.-E., Aguzzi, A., Ajami, B., Amit, I., Audinat, E., Bechmann, I.,

Bennett, M., Bennett, F., Bessis, A., Biber, K., Bilbo, S., Blurton-Jones, M., Boddeke, E., Brites, D., Brône, B.,

Brown, G. C., Butovsky, O., Carson, M. J., Castellano, B., Colonna, M., Cowley, S. A., Cunningham, C., Davalos, D.,

De Jager, P. L., de Strooper, B., Denes, A., Eggen, B. J. L., Eyo, U., Galea, E., Garel, S., Ginhoux, F., Glass, C. K.,

Gokce, O., Gomez-Nicola, D., González, B., Gordon, S., Graeber, M. B., Greenhalgh, A. D., Gressens, P., Greter, M.,

Gutmann, D.H., Haass, C., Heneka, M. T., Heppner, F. L., Hong, S., Hume, D. A., Jung,S., Ketenmann, H., Kipnis, J.,

Koyama, R., Lemke, G., Lynch, M., Majewska, A., Malcangio, M., Malm, T., Mancuso, R., Masuda, T., Matteoli, M.,

McColl, B. W., Miron, V. E., Molofsky, A. V., Monje, M., Mracsko, E., Nadjar, A., Neher, J. J., Neniskyte, U.,

Neumann, H., Noda, M., Peng, B., Peri, F., Perry, V. H., Popovich, P. G., Pridans, C., Priller, J., Prinz, M.,

METABOLIC REPROGRAMMING OF GLIA IN EPILEPTOGENESIS 757

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

Ragozzino, D., Ransohoff, R. M., Salter, M. W., Schaefer, A., Schafer, D. P., Schwartz, M., Simons, M., Smith, C. J.,

Streit, W. J., Tay, T. L., Tsai, L.-H., Verkhratsky, A., von Bernhardi, R., Wake,H., Wittamer, V., Wolf, S. A., Wu, L.-J.,

and Wyss-Coray, T. (2022) Microglia states and nomenclature: a field at its crossroads, Neuron, 110, 3458-3483,

https://doi.org/10.1016/j.neuron.2022.10.020.

18. Ransohoff, R. M. (2016) A polarizing question: do M1 and M2 microglia exist? Nat. Neurosci., 19, 987-991, https://

doi.org/10.1038/nn.4338.

19. Pellerin, L., and Magistretti, P. J. (2012) Sweet sixteen for ANLS, J. Cereb. Blood Flow Metab., 32, 1152-1166,

https://doi.org/10.1038/jcbfm.2011.149.

20. Vezzani, A., Ravizza, T., Bedner, P., Aronica, E., Steinhäuser, C., and Boison, D. (2022) Astrocytes in the initiation

and progression of epilepsy, Nat. Rev. Neurol., 18, 707-722, https://doi.org/10.1038/s41582-022-00727-5.

21. Hu, Y., Mai, W., Chen, L., Cao, K., Zhang, B., Zhang, Z., Liu, Y., Lou, H., Duan, S., and Gao, Z. (2020) mTOR-me-

diated metabolic reprogramming shapes distinct microglia functions in response to lipopolysaccharide and ATP,

Glia, 68, 1031-1045, https://doi.org/10.1002/glia.23760.

22. Boison, D., and Steinhäuser, C. (2018) Epilepsy and astrocyte energy metabolism, Glia, 66, 1235-1243, https://

doi.org/10.1002/glia.23247.

23. Cavus, I., Kasoff, W. S., Cassaday, M. P., Jacob, R., Gueorguieva, R., Sherwin, R. S., Krystal, J. H., Spencer, D. D.,

and Abi-Saab, W. M. (2005) Extracellular metabolites in the cortex and hippocampus of epileptic patients, Ann.

Neurol., 57, 226-235, https://doi.org/10.1002/ana.20380.

24. Chen, X., and Zhu,X. (2025) Lactate: beyond a mere fuel in the epileptic brain, Neuropharmacology, 266, 110273,

https://doi.org/10.1016/j.neuropharm.2024.110273.

25. Pate, K. T., Stringari, C., Sprowl-Tanio, S., Wang, K., TeSlaa, T., Hoverter, N. P., McQuade, M. M., Garner, C.,

Digman, M. A., Teitell, M. A., Edwards, R. A., Gratton, E., and Waterman, M. L. (2014) Wnt signaling directs

a metabolic program of glycolysis and angiogenesis in colon cancer, EMBO J., 33, 1454-1473, https://doi.org/

10.15252/embj.201488598.

26. Palsson-McDermott, E. M., and O’Neill, L. A. J. (2013) The Warburg effect then and now: from cancer to inflam-

matory diseases, Bioessays, 35, 965-973, https://doi.org/10.1002/bies.201300084.

27. Yang, H., Wu, J., Guo, R., Peng, Y., Zheng, W., Liu, D., and Song, Z. (2013) Glycolysis in energy metabolism during

seizures, Neural Regen. Res., 8, 1316-1326, https://doi.org/10.4103/1673-5374.121652.

28. Malkov, A., Ivanov, A. I., Buldakova, S., Waseem, T., Popova, I., Zilberter, M., and Zilberter, Y. (2018) Seizure-in-

duced reduction in glucose utilization promotes brain hypometabolism during epileptogenesis, Neurobiol. Dis.,

116, 28-38, https://doi.org/10.1016/j.nbd.2018.04.016.

29. Alqurashi, R. S., Yee, A. S., Malone, T., Alrubiaan, S., Tam, M. W., Wang, K., Nandedwalla, R. R., Field, W.,

Alkhelb, D., Given, K. S., Siddiqui, R., Baleja, J. D., Paulson, K. E., and Yee, A. S. (2021) A Warburg-like metabolic

program coordinates Wnt, AMPK, and mTOR signaling pathways in epileptogenesis, PLoS One, 16, e0252282,

https://doi.org/10.1371/journal.pone.0252282.

30. Inoki, K., Ouyang, H., Zhu, T., Lindvall, C., Wang, Y., Zhang, X., Yang, Q., Bennett, C., Harada, Y., Stankunas, K.,

Wang, C.-Y., He, X., MacDougald, O. A., You, M., Williams, B. O., and Guan, K.-L. (2006) TSC2 integrates Wnt and

energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth, Cell, 126, 955-968,

https://doi.org/10.1016/j.cell.2006.06.055.

31. Hardie, D. G., and Ashford, M. L. J. (2014) AMPK: regulating energy balance at the cellular and whole body

levels, Physiology, 29, 99-107, https://doi.org/10.1152/physiol.00050.2013.

32. Crino, P. B. (2019) Mechanistic target of rapamycin (mTOR) signaling in status epilepticus, Epilepsy Behav., 101,

106550, https://doi.org/10.1016/j.yebeh.2019.106550.

33. Hu, Y., Cao, K., Wang, F., Wu, W., Mai, W., Qiu, L., Luo, Y., Ge, W.-P., Sun, B., Shi, L., Zhu, J., Zhang, J., Wu, Z.,

Xie, Y., Duan, S., and Gao, Z. (2022) Dual roles of hexokinase 2 in shaping microglial function by gating glyco-

lytic flux and mitochondrial activity, Nat. Metab., 4, 1756-1774, https://doi.org/10.1038/s42255-022-00707-5.

34. Chao, C.-C., Gutiérrez-Vázquez, C., Rothhammer, V., Mayo,L., Wheeler, M. A., Tjon, E. C., Zandee, S. E. J., Blain,M.,

de Lima, K. A., Takenaka, M.C., Avila-Pacheco, J., Hewson, P., Liu, L., Sanmarco, L.M., Borucki, D.M., Lipof, G. Z.,

Trauger, S. A., Clish, C. B., Antel, J. P., Prat, A., and Quintana, F. J. (2019) Metabolic control of astrocyte patho-

genic activity via cPLA2-MAVS, Cell, 179, 1483-1498, https://doi.org/10.1016/j.cell.2019.11.016.

35. Stobart, J. L., and Anderson, C. M. (2013) Multifunctional role of astrocytes as gatekeepers of neuronal energy

supply, Front. Cell. Neurosci., 7, 38, https://doi.org/10.3389/fncel.2013.00038.

36. Dienel, G. A., Gillinder, L., McGonigal, A., and Borges, K. (2023) Potential new roles for glycogen in epilepsy,

Epilepsia, 64, 29-53, https://doi.org/10.1111/epi.17412.

37. Rho, J. M., Shao, L.-R., and Stafstrom, C. E. (2019) 2-Deoxyglucose and beta-hydroxybutyrate: metabolic agents

for seizure control, Front. Cell. Neurosci., 13, 172, https://doi.org/10.3389/fncel.2019.00172.

ZAKHAROVA et al.758

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

38. Cheong, J.-H., Park, E. S., Liang, J., Dennison, J. B., Tsavachidou, D., Nguyen-Charles, C., Wa Cheng, K., Hall, H.,

Zhang, D., Lu, Y., Ravoori, M., Kundra, V., Ajani, J., Lee, J.-S., Ki Hong, W., and Mills, G. B. (2011) Dual inhibition

of tumor energy pathway by 2-deoxyglucose and metformin is effective against a broad spectrum of preclinical

cancer models, Mol. Cancer Ther., 10, 2350-2362, https://doi.org/10.1158/1535-7163.MCT-11-0497.

39. Zhang, Y., Chen, K., Sloan, S. A., Bennett, M. L., Scholze, A. R., O’Keeffe, S., Phatnani, H. P., Guarnieri, P.,

Caneda, C., Ruderisch, N., Deng, S., Liddelow, S. A., Zhang, C., Daneman, R., Maniatis, T., Barres, B. A., and

Wu, J. Q. (2014) An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells

of the cerebral cortex, J. Neurosci., 34, 11929-11947, https://doi.org/10.1523/JNEUROSCI.1860-14.2014.

40. Zhang, Z., Deng, X., Liu, Y., Liu, Y., Sun, L., and Chen, F. (2019) PKM2, function and expression and regulation,

Cell Biosci., 9, 52, https://doi.org/10.1186/s13578-019-0317-8.

41. Li, H., Sun, L., Gao, P., and Hu, H. (2024) Lactylation in cancer: Current understanding and challenges, Cancer

Cell, 42, 1803-1807, https://doi.org/10.1016/j.ccell.2024.09.006.

42. Pan, R.-Y., He, L., Zhang, J., Liu, X., Liao, Y., Gao, J., Liao, Y., Yan, Y., Li, Q., Zhou, X., Cheng, J., Xing, Q.,

Guan, F., Zhang, J., Sun, L., and Yuan, Z. (2022) Positive feedback regulation of microglial glucose metabolism

by histone H4 lysine 12 lactylation in Alzheimer’s disease, Cell Metab., 34, 634-648, https://doi.org/10.1016/j.cmet.

2022.02.013.

43. Zhang, Q., Wang, S.-S., Zhang, Z., and Chu, S.-F. (2025) PKM2-mediated metabolic reprogramming of microglia

in neuroinflammation, Cell Death Discov., 11, 149, https://doi.org/10.1038/s41420-025-02453-5.

44. Lu, L., Wang, H., Liu, X., Tan, L., Qiao, X., Ni, J., Sun, Y., Liang, J., Hou, Y., and Dou, H. (2021) Pyruvate kinase

isoform M2 impairs cognition in systemic lupus erythematosus by promoting microglial synaptic pruning via

the β-catenin signaling pathway, J. Neuroinflammation, 18, 229, https://doi.org/10.1186/s12974-021-02279-9.

45. Zhu, H., Zhang, H., Zhao, X.-J., Zhang, L., Liu, X., Zhang, Z.-Y., Ren, Y.-Z., and Feng, Y. (2024) Tetramerization of

PKM2 alleviates traumatic brain injury by ameliorating mitochondrial damage in microglia, J. Neuroimmune

Pharmacol., 19, 48, https://doi.org/10.1007/s11481-024-10138-6.

46. Fei, Y., Shi, R., Song, Z., and Wu, J. (2020) Metabolic control of epilepsy: a promising therapeutic target for

epilepsy, Front. Neurol., 11, 592514, https://doi.org/10.3389/fneur.2020.592514.

47. Di Stefano, G., Manerba, M., Di Ianni, L., and Fiume, L. (2016) Lactate dehydrogenase inhibition: explor-

ing possible applications beyond cancer treatment, Future Med. Chem., 8, 713-725, https://doi.org/10.4155/

fmc.16.10.

48. Sada, N., Lee, S., Katsu, T., Otsuki, T., and Inoue, T. (2015) Epilepsy treatment. Targeting LDH enzymes with a

stiripentol analog to treat epilepsy, Science, 347, 1362-1367, https://doi.org/10.1126/science.aaa1299.

49. Nickels, K.C., and Wirrell, E. C. (2017) Stiripentol in the management of epilepsy, CNS Drugs, 31, 405-416, https://

doi.org/10.1007/s40263-017-0432-1.

50. Deng, H., Brewer, S., Vu, D. M., Clinch, K., Callender, R., and Dyer, R. B. (2008) On the pathway of forming

enzymatically productive ligand-protein complexes in lactate dehydrogenase, Biophys. J., 95, 804-813, https://

doi.org/10.1529/biophysj.108.128884.

51. Pan, Y.-Z., Sutula, T. P., and Rutecki, P. A. (2019) 2-Deoxy-d-glucose reduces epileptiform activity by presynaptic

mechanisms, J. Neurophysiol., 121, 1092-1101, https://doi.org/10.1152/jn.00723.2018.

52. Stafstrom, C. E., Ockuly, J. C., Murphree, L., Valley, M. T., Roopra, A., and Sutula, T. P. (2009) Anticonvulsant

and antiepileptic actions of 2-deoxy-D-glucose in epilepsy models, Ann. Neurol., 65, 435-447, https://doi.org/

10.1002/ana.21603.

53. Yang, H., Guo, R., Wu, J., Peng, Y., Xie, D., Zheng, W., Huang, X., Liu, D., Liu, W., Huang, L., and Song, Z.

(2013) The antiepileptic effect of the glycolytic inhibitor 2-deoxy-D-glucose is mediated by upregulation

of K(ATP) channel subunits Kir6.1 and Kir6.2, Neurochem. Res., 38, 677-685, https://doi.org/10.1007/s11064-

012-0958-z.

54. Khatibi, V. A., Rahdar, M., Rezaei, M., Davoudi, S., Nazari, M., Mohammadi, M., Raoufy, M. R., Mirnajafi-Zadeh, J.,

Hosseinmardi, N., Behzadi, G., and Janahmadi, M. (2023) The glycolysis inhibitor 2-deoxy-D-glucose exerts differ-

ent neuronal effects at circuit and cellular levels, partially reverses behavioral alterations and does not prevent

NADPH diaphorase activity reduction in the intrahippocampal kainic acid model of temporal lobe epilepsy,

Neurochem. Res., 48, 210-228, https://doi.org/10.1007/s11064-022-03740-8.

55. Auvin, S., Lecointe, C., Dupuis, N., Desnous, B., Lebon, S., Gressens, P., and Dournaud, P. (2013) Stiripentol ex-

hibits higher anticonvulsant properties in the immature than in the mature rat brain, Epilepsia, 54, 2082-2090,

https://doi.org/10.1111/epi.12401.

56. Ji, D., Mylvaganam, S., Ravi Chander, P., Tarnopolsky, M., Murphy, K., and Carlen, P. (2024) Mitochondria and

oxidative stress in epilepsy: advances in antioxidant therapy, Front. Pharmacol., 15, 1505867, https://doi.org/

10.3389/fphar.2024.1505867.

METABOLIC REPROGRAMMING OF GLIA IN EPILEPTOGENESIS 759

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

57. Miao, J., Chen, L., Pan, X., Li, L., Zhao, B., and Lan, J. (2023) Microglial metabolic reprogramming: emerging

insights and therapeutic strategies in neurodegenerative diseases, Cell. Mol. Neurobiol., 43, 3191-3210, https://

doi.org/10.1007/s10571-023-01376-y.

58. Bao, Y., Hu, C., Wang, B., Liu, X., Wu, Q., Xu, D., Shi, Z., and Sun, C. (2025) Mitochondrial reverse electron

transport: mechanisms, pathophysiological roles, and therapeutic potential, Biology, 14, 9, https://doi.org/10.3390/

biology14091140.

59. Xu, L., Zhao, Z., Zhang, Y., and Ma, C. (2025) The interplay between metabolism and neuroinflammation in

epilepsy: mechanisms and therapeutic perspectives, J. Neuroinflammation, 22, 265, https://doi.org/10.1186/s12974-

025-03553-w.

60. Geronzi, U., Lotti, F., and Grosso, S. (2018) Oxidative stress in epilepsy, Expert Rev. Neurother., 18, 427-434,

https://doi.org/10.1080/14737175.2018.1465410.

61. Turrens, J. F. (2003) Mitochondrial formation of reactive oxygen species, J. Physiol., 552, 335-344, https://

doi.org/10.1113/jphysiol.2003.049478.

62. Jarrett, S. G., Liang, L.-P., Hellier, J. L., Staley, K. J., and Patel, M. (2008) Mitochondrial DNA damage and im-

paired base excision repair during epileptogenesis, Neurobiol. Dis., 30, 130-138, https://doi.org/10.1016/j.nbd.

2007.12.009.

63. Pearson-Smith, J. N., and Patel, M. (2017) Metabolic dysfunction and oxidative stress in epilepsy, Int. J. Mol. Sci.,

18, 11, https://doi.org/10.3390/ijms18112365.

64. Pestana, R. R. F., Kinjo, E. R., Hernandes, M. S., and Britto, L. R. G. (2010) Reactive oxygen species generated by

NADPH oxidase are involved in neurodegeneration in the pilocarpine model of temporal lobe epilepsy, Neurosci.

Lett., 484, 187-191, https://doi.org/10.1016/j.neulet.2010.08.049.

65. Pauletti, A., Terrone, G., Shekh-Ahmad, T., Salamone, A., Ravizza,T., Rizzi, M., Pastore, A., Pascente,R., Liang, L.-P.,

Villa, B. R., Balosso, S., Abramov, A. Y., van Vliet, E. A., Del Giudice, E., Aronica, E., Patel, M., Walker, M. C., and

Vezzani, A. (2019) Targeting oxidative stress improves disease outcomes in a rat model of acquired epilepsy,

Brain, 142, e39, https://doi.org/10.1093/brain/awz130.

66. Xavier, S. M., Barbosa, C. O., Barros, D. O., Silva, R. F., Oliveira, A. A., and Freitas, R. M. (2007) Vitamin  C anti-

oxidant effects in hippocampus of adult Wistar rats after seizures and status epilepticus induced by pilocarpine,

Neurosci. Lett., 420, 76-79, https://doi.org/10.1016/j.neulet.2007.04.056.

67. Ahmad, M. (2013) Protective effects of curcumin against lithium-pilocarpine induced status epilepticus, cog-

nitive dysfunction and oxidative stress in young rats, Saudi J. Biol. Sci., 20, 155-162, https://doi.org/10.1016/

j.sjbs.2013.01.002.

68. Pearson, J. N., Rowley, S., Liang, L.-P., White, A. M., Day, B. J., and Patel, M. (2015) Reactive oxygen species medi-

ate cognitive deficits in experimental temporal lobe epilepsy, Neurobiol. Dis., 82, 289-297, https://doi.org/10.1016/

j.nbd.2015.07.005.

69. Ahmad, M., Abu-Taweel, G. M., Aboshaiqah, A. E., and Ajarem, J. S. (2014) The effects of quinacrine, proglumide,

and pentoxifylline on seizure activity, cognitive deficit, and oxidative stress in rat lithium-pilocarpine model of

status epilepticus, Oxid. Med. Cell. Longev., 2014, 630509, https://doi.org/10.1155/2014/630509.

70. Ambrogini, P., Minelli, A., Galati, C., Betti, M., Lattanzi, D., Ciffolilli, S., Piroddi, M., Galli, F., and Cuppini, R.

(2014) Post-seizure α-tocopherol treatment decreases neuroinflammation and neuronal degeneration in-

duced by status epilepticus in rat hippocampus, Mol. Neurobiol., 50, 246-256, https://doi.org/10.1007/s12035-

014-8648-2.

71. Liang, L. P., Ho, Y. S., and Patel, M. (2000) Mitochondrial superoxide production in kainate-induced hippocampal

damage, Neuroscience, 101, 563-570, https://doi.org/10.1016/S0306-4522(00)00397-3.

72. Tarnopolsky, M. A. (2008) The mitochondrial cocktail: rationale for combined nutraceutical therapy in mitochon-

drial cytopathies, Adv. Drug Deliv. Rev., 60, 1561-1567, https://doi.org/10.1016/j.addr.2008.05.001.

73. Kovac, S., Domijan, A.-M., Walker, M. C., and Abramov, A. Y. (2014) Seizure activity results in calcium- and mi-

tochondria-independent ROS production via NADPH and xanthine oxidase activation, Cell Death Dis., 5, e1442,

https://doi.org/10.1038/cddis.2014.390.

74. Kim, J. H., Jang, B. G., Choi, B. Y., Kim, H. S., Sohn, M., Chung, T. N., Choi, H. C., Song, H. K., and Suh, S. W.

(2013) Post-treatment of an NADPH oxidase inhibitor prevents seizure-induced neuronal death, Brain Res., 1499,

163-172, https://doi.org/10.1016/j.brainres.2013.01.007.

75. Patel, M., Li, Q.-Y., Chang, L.-Y., Crapo, J., and Liang, L.-P. (2005) Activation of NADPH oxidase and extracellu-

lar superoxide production in seizure-induced hippocampal damage, J. Neurochem., 92, 123-131, https://doi.org/

10.1111/j.1471-4159.2004.02838.x.

76. Cinelli, M. A., Do, H. T., Miley, G. P., and Silverman, R. B. (2020) Inducible nitric oxide synthase: Regulation,

structure, and inhibition, Med. Res. Rev., 40, 158-189, https://doi.org/10.1002/med.21599.

ZAKHAROVA et al.760

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

77. Catania, M. V., Giuffrida, R., Seminara, G., Barbagallo, G., Aronica, E., Gorter, J. A., Dell’Albani, P., Ravagna, A.,

Calabrese, V., and Giuffrida-Stella, A. M. (2003) Upregulation of neuronal nitric oxide synthase in in  vitro stel-

late astrocytes and in vivo reactive astrocytes after electrically induced status epilepticus, Neurochem. Res., 28,

607-615, https://doi.org/10.1023/A:1022841911265.

78. Cosgrave, A. S., McKay, J. S., Bubb, V., Morris, R., Quinn, J. P., and Thippeswamy, T. (2008) Regulation of ac-

tivity-dependent neuroprotective protein (ADNP) by the NO-cGMP pathway in the hippocampus during kainic

acid-induced seizure, Neurobiol. Dis., 30, 281-292, https://doi.org/10.1016/j.nbd.2008.02.005.

79. Meskinimood, S., Rahimi, N., Faghir-Ghanesefat, H., Gholami, M., Sharifzadeh, M., and Dehpour, A. R. (2019)

Modulatory effect of opioid ligands on status epilepticus and the role of nitric oxide pathway, Epilepsy Behav.,

101, 106563, https://doi.org/10.1016/j.yebeh.2019.106563.

80. Banach, M., Piskorska, B., Czuczwar, S. J., and Borowicz, K. K. (2011) Nitric oxide, epileptic seizures, and action

of antiepileptic drugs, CNS Neurol. Disord. Drug Targets, 10, 808-819, https://doi.org/10.2174/187152711798072347.

81. Rehni, A. K., Singh, T. G., Kalra, R., and Singh, N. (2009) Pharmacological inhibition of inducible nitric ox-

ide synthase attenuates the development of seizures in mice, Nitric Oxide Biol. Chem., 21, 120-125, https://

doi.org/10.1016/j.niox.2009.06.001.

82. Puttachary, S., Sharma, S., Verma, S., Yang, Y., Putra, M., Thippeswamy, A., Luo, D., and Thippeswamy, T.

(2016) 1400W, a highly selective inducible nitric oxide synthase inhibitor is a potential disease modifier in

the rat kainate model of temporal lobe epilepsy, Neurobiol. Dis., 93, 184-200, https://doi.org/10.1016/j.nbd.

2016.05.013.

83. Li, H.-S., Zhou, Y.-N., Li, L., Li, S.-F., Long, D., Chen, X.-L., Zhang, J.-B., Feng, L., and Li, Y.-P. (2019) HIF-1α

protects against oxidative stress by directly targeting mitochondria, Redox Biol., 25, 101109, https://doi.org/

10.1016/j.redox.2019.101109.

84. Liang, Z., Guo, Q., Zheng, Z., Lou, Y., Zhu, X., and Liu, S. (2025) Hypoxia-inducible factor 1α inhibitor reduces

hippocampal neuronal ferroptosis, Neural Regen. Res., 21, 2389-2396, https://doi.org/10.4103/NRR.NRR-D-24-01007.

85. Li, Y., Wu, L., Yu, M., Yang, F., Wu, B., Lu, S., Tu, M., and Xu, H. (2018) HIF-1α is critical for the activation

of notch signaling in neurogenesis during acute epilepsy, Neuroscience, 394, 206-219, https://doi.org/10.1016/

j.neuroscience.2018.10.037.

86. Freeman, L. C., and Ting, J. P.-Y. (2016) The pathogenic role of the inflammasome in neurodegenerative diseases,

J. Neurochem., 136, 29-38, https://doi.org/10.1111/jnc.13217.

87. Younger, D., Murugan, M., Rama Rao, K. V., Wu, L.-J., and Chandra, N. (2019) Microglia receptors in animal

models of traumatic brain injury, Mol. Neurobiol., 56, 5202-5228, https://doi.org/10.1007/s12035-018-1428-7.

88. Lu, Y., Yang, Y.-Y., Zhou, M.-W., Liu, N., Xing, H.-Y., Liu, X.-X., and Li, F. (2018) Ketogenic diet attenuates oxida-

tive stress and inflammation after spinal cord injury by activating Nrf2 and suppressing the NF-κB signaling

pathways, Neurosci. Lett., 683, 13-18, https://doi.org/10.1016/j.neulet.2018.06.016.

89. Yussra, A. Y. A., Hala Salah, A. K., Huda, M. A., and Nisreen, A. R. (2021) The potential antiepileptic activity

of astaxanthin in epileptic rats treated with valproic acid, Saudi Pharm. J., 29, 418-426, https://doi.org/10.1016/

j.jsps.2021.04.002.

90. Imam, A., Tunde, A. M., Amin, A., Abdulmajeed, W. I., Attai, A. G., Akorede, A. A., Ijomone, O.M., and Ajao, M. S.

(2025) Vitamin E-valproate co-therapy attenuated oxidative stress, neuroinflammation, related cognitive defi-

cits and neuronal damage in Cypermethrin exacerbated seizure, BMC Pharmacol. Toxicol., 26, 184, https://

doi.org/10.1186/s40360-025-01027-6.

91. Kamsler, A., and Segal, M. (2004) Hydrogen peroxide as a diffusible signal molecule in synaptic plasticity, Mol.

Neurobiol., 29, 167-178, https://doi.org/10.1385/MN:29:2:167.

92. Beckhauser, T. F., Francis-Oliveira, J., and De Pasquale, R. (2016) Reactive oxygen species: physiological and

physiopathological effects on synaptic plasticity, J. Exp. Neurosci., 10, 23-48, https://doi.org/10.4137/JEN.S39887.

93. Bonvento, G., and Bolaños, J. P. (2021) Astrocyte-neuron metabolic cooperation shapes brain activity, Cell Metab.,

33, 1546-1564, https://doi.org/10.1016/j.cmet.2021.07.006.

94. Salvagno, M., Sterchele, E. D., Zaccarelli, M., Mrakic-Sposta, S., Welsby, I. J., Balestra, C., and Taccone, F. S. (2024)

Oxidative stress and cerebral vascular tone: the role of reactive oxygen and nitrogen species, Int. J. Mol. Sci.,

25, 5, https://doi.org/10.3390/ijms25053007.

95. Yildirim, M., and Marangoz, C. (2006) Anticonvulsant effects of melatonin on penicillin-induced epileptiform

activity in rats, Brain Res., 1099, 183-188, https://doi.org/10.1016/j.brainres.2006.04.093.

96. Tchekalarova,J., Petkova, Z., Pechlivanova, D., Moyanova, S., Kortenska, L., Mitreva, R., Lozanov, V., Atanasova, D.,

Lazarov, N., and Stoynev, A. (2013) Prophylactic treatment with melatonin after status epilepticus: effects on

epileptogenesis, neuronal damage, and behavioral changes in a kainate model of temporal lobe epilepsy, Epilepsy

Behav., 27, 174-187, https://doi.org/10.1016/j.yebeh.2013.01.009.

METABOLIC REPROGRAMMING OF GLIA IN EPILEPTOGENESIS 761

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

97. Hosseinzadeh, A., Dehdashtian, E., Jafari-Sabet, M., and Mehrzadi, S. (2022) The effects of vitamin D3 and mel-

atonin combination on pentylenetetrazole-induced seizures in mice, Cent. Nerv. Syst. Agents Med. Chem., 22,

118-124, https://doi.org/10.2174/1871524922666220429121253.

98. Mosińska, P., Socała, K., Nieoczym, D., Laudon, M., Storr, M., Fichna, J., and Wlaź, P. (2016) Anticonvulsant ac-

tivity of melatonin, but not melatonin receptor agonists Neu-P11 and Neu-P67, in mice, Behav. Brain Res., 307,

199-207, https://doi.org/10.1016/j.bbr.2016.03.036.

99. Ambrogini, P., Albertini, M. C., Betti, M., Galati, C., Lattanzi, D., Savelli, D., Di Palma, M., Saccomanno, S.,

Bartolini, D., Torquato, P., Ruffolo, G., Olivieri, F., Galli, F., Palma, E., Minelli, A., and Cuppini, R. (2018) Neu-

robiological correlates of alpha-tocopherol antiepileptogenic effects and microRNA expression modulation

in a rat model of kainate-induced seizures, Mol. Neurobiol., 55, 7822-7838, https://doi.org/10.1007/s12035-

018-0946-7.

100. Zhang, X., Wu, S., Guo, C., Guo, K., Hu, Z., Peng, J., Zhang, Z., and Li, J. (2022) Vitamin E exerts neuroprotec-

tive effects in pentylenetetrazole kindling epilepsy via suppression of ferroptosis, Neurochem. Res., 47, 739-747,

https://doi.org/10.1007/s11064-021-03483-y.

101. Tomé, A. R., Feng, D., and Freitas, R. M. (2010) The effects of alpha-tocopherol on hippocampal oxidative

stress prior to in pilocarpine-induced seizures, Neurochem. Res., 35, 580-587, https://doi.org/10.1007/s11064-

009-0102-x.

102. Tomé, A. R., Ferreira, P. M. P., and Freitas, R. M. (2010) Inhibitory action of antioxidants (ascorbic acid or al-

pha-tocopherol) on seizures and brain damage induced by pilocarpine in rats, Arq. Neuropsiquiatr., 68, 355-361,

https://doi.org/10.1590/S0004-282X2010000300005.

103. Schneider Oliveira, M., Flávia Furian, A., Freire Royes, L. F., Rechia Fighera, M., de Carvalho Myskiw, J.,

Gindri Fiorenza, N., and Mello, C. F. (2004) Ascorbate modulates pentylenetetrazol-induced convulsions biphasi-

cally, Neuroscience, 128, 721-728, https://doi.org/10.1016/j.neuroscience.2004.07.012.

104. Xu, K., and Stringer, J. L. (2008) Antioxidants and free radical scavengers do not consistently delay seizure onset

in animal models of acute seizures, Epilepsy Behav., 13, 77-82, https://doi.org/10.1016/j.yebeh.2008.03.002.

105. Tomé, A. R., Feitosa, C. M., and Freitas, R. M. (2010) Neuronal damage and memory deficits after seizures are

reversed by ascorbic acid? Arq. Neuropsiquiatr., 68, 579-585, https://doi.org/10.1590/S0004-282X2010000400019.

106. Ullah, I., Badshah, H., Naseer, M. I., Lee, H. Y., and Kim, M. O. (2015) Thymoquinone and vitamin C attenuates

pentylenetetrazole-induced seizures via activation of GABAB1 receptor in adult rats cortex and hippocampus,

Neuromol. Med., 17, 35-46, https://doi.org/10.1007/s12017-014-8337-3.

107. Kaur, H., Bal, A., and Sandhir, R. (2014) Curcumin supplementation improves mitochondrial and behavioral

deficits in experimental model of chronic epilepsy, Pharmacol. Biochem. Behav., 125, 55-64, https://doi.org/

10.1016/j.pbb.2014.08.001.

108. Hong, S., GuoYan, L., JiaWen, W., Xin, Y., ShuQin, Z., HongWei, R., MengYing, C., and YuXuan, C. (2025) Curcumin

prevents neuronal loss and inhibits development of spontaneous recurrent seizures via the PPARγ/PTEN/Akt

pathway in chronic epilepsy, J. Neurosci. Res., 103, e70064, https://doi.org/10.1002/jnr.70064.

109. Li, Z., You, Z., Li, M., Pang, L., Cheng, J., and Wang, L. (2017) Protective effect of resveratrol on the brain in a

rat model of epilepsy, Neurosci. Bull., 33, 273-280, https://doi.org/10.1007/s12264-017-0097-2.

110. Meng, X. J., Wang, F., and Li, C. K. (2014) Resveratrol is neuroprotective and improves cognition in penty-

lenetetrazole-kindling model of epilepsy in rats, Indian J. Pharm. Sci., 76, 125-131.

111. Xing, J., Han, D., Xu, D., Li, X., and Sun, L. (2019) CREB protects against temporal lobe epilepsy associated

with cognitive impairment by controlling oxidative neuronal damage, Neurodegener. Dis., 19, 225-237, https://

doi.org/10.1159/000507023.

112. Liang, L.-P., Waldbaum, S., Rowley, S., Huang, T.-T., Day, B. J., and Patel, M. (2012) Mitochondrial oxidative stress

and epilepsy in SOD2 deficient mice: attenuation by a lipophilic metalloporphyrin, Neurobiol. Dis., 45, 1068-1076,

https://doi.org/10.1016/j.nbd.2011.12.025.

113. Shekh-Ahmad, T., Lieb, A., Kovac, S., Gola, L., Christian Wigley, W., Abramov, A. Y., and Walker, M. C. (2019)

Combination antioxidant therapy prevents epileptogenesis and modifies chronic epilepsy, Redox Biol., 26, 101278,

https://doi.org/10.1016/j.redox.2019.101278.

114. Efendioglu, M., Basaran, R., Akca, M., Ceman, D., Demirtas, C., and Yildirim, M. (2020) Combination therapy of

gabapentin and n-acetylcysteine against posttraumatic epilepsy in rats, Neurochem. Res., 45, 1802-1812, https://

doi.org/10.1007/s11064-020-03042-x.

115. Tastan, B., and Heneka, M. T. (2024) The impact of neuroinflammation on neuronal integrity, Immunol. Rev.,

327, 8-32, https://doi.org/10.1111/imr.13419.

116. Rana, A., and Musto, A. E. (2018) The role of inflammation in the development of epilepsy, J. Neuroinflamma-

tion, 15, 144, https://doi.org/10.1186/s12974-018-1192-7.

ZAKHAROVA et al.762

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

117. Sanz, P., Rubio, T., and Garcia-Gimeno, M. A. (2024) Neuroinflammation and epilepsy: from pathophysiology

to therapies based on repurposing drugs, Int. J. Mol. Sci., 25, 4161, https://doi.org/10.3390/ijms25084161.

118. Patel, D. C., Tewari, B. P., Chaunsali, L., and Sontheimer, H. (2019) Neuron-glia interactions in the pathophysi-

ology of epilepsy, Nat Rev Neurosci., 20, 282-297, https://doi.org/10.1038/s41583-019-0126-4.

119. Vezzani, A., French, J., Bartfai, T., and Baram, T. Z. (2011) The role of inflammation in epilepsy, Nat. Rev. Neu-

rol., 7, 31-40, https://doi.org/10.1038/nrneurol.2010.178.

120. Ravizza, T., Gagliardi, B., Noé, F., Boer, K., Aronica, E., and Vezzani, A. (2008) Innate and adaptive immunity

during epileptogenesis and spontaneous seizures: evidence from experimental models and human temporal lobe

epilepsy, Neurobiol. Dis., 29, 142-160, https://doi.org/10.1016/j.nbd.2007.08.012.

121. Huang, Y., Xu, W., and Zhou, R. (2021) NLRP3 inflammasome activation and cell death, Cell. Mol. Immunol., 18,

2114-2127, https://doi.org/10.1038/s41423-021-00740-6.

122. Swanson, K. V., Deng, M., and Ting, J. P.-Y. (2019) The NLRP3 inflammasome: molecular activation and regulation

to therapeutics, Nat. Rev. Immunol., 19, 477-489, https://doi.org/10.1038/s41577-019-0165-0.

123. Xu, W., Huang, Y., and Zhou, R. (2025) NLRP3 inflammasome in neuroinflammation and central nervous system

diseases, Cell. Mol. Immunol., 22, 341-355, https://doi.org/10.1038/s41423-025-01275-w.

124. Pohlentz, M. S., Müller, P., Cases-Cunillera, S., Opitz, T., Surges, R., Hamed, M., Vatter, H., Schoch, S., Becker, A. J.,

and Pitsch, J. (2022) Characterisation of NLRP3 pathway-related neuroinflammation in temporal lobe epilepsy,

PLoS One, 17, e0271995, https://doi.org/10.1371/journal.pone.0271995.

125. Chen, J., Gao, Y., Liu, N., Hai, D., Wei, W., Liu, Y., Lan, X., Jin, X., Yu, J., and Ma, L. (2024) Mechanism of

NLRP3 inflammasome in epilepsy and related therapeutic agents, Neuroscience, 546, 157-177, https://doi.org/

10.1016/j.neuroscience.2024.03.029.

126. Aghaie, F., Moradifar, F., and Hosseini, A. (2021) Rapamycin attenuates depression and anxiety-like behaviors

through modulation of the NLRP3 pathway in pentylenetetrazole-kindled male Wistar rats, Fundam. Clin. Phar-

macol., 35, 1045-1054, https://doi.org/10.1111/fcp.12689.

127. Samadianzakaria, A., Abdolmaleki, Z., and Faedmaleki, F. (2022) The effect of valproic acid and furosemide on

the regulation of the inflammasome complex (NLRP1 and NLRP3 mRNA) in the brain of epileptic animal model,

Brain Res. Bull., 191, 20-29, https://doi.org/10.1016/j.brainresbull.2022.10.002.

128. Jiang, H., He, H., Chen, Y., Huang, W., Cheng, J., Ye, J., Wang, A., Tao, J., Wang, C., Liu, Q., Jin, T., Jiang, W.,

Deng, X., and Zhou, R. (2017) Identification of a selective and direct NLRP3 inhibitor to treat inflammatory

disorders, J. Exp. Med., 214, 3219-3238, https://doi.org/10.1084/jem.20171419.

129. Shen,K., Jiang, W., Zhang, C., Cai, L., Wang, Q., Yu, H., Tang, Z., Gu, Z., and Chen, B. (2021) Molecular mechanism

of a specific NLRP3 inhibitor to alleviate seizure severity induced by pentylenetetrazole, Curr. Mol. Pharmacol.,

14, 579-586, https://doi.org/10.2174/1874467213666200810140749.

130. He, N., Zheng, X., He, T., Shen, G., Wang, K., Hu, J., Zheng, M., Ding, Y., Song, X., Zhong, J., Chen, Y.-Y., Wang,

L.-L., and Yueliang, S. (2021) MCC950 reduces neuronal apoptosis in spinal cord injury in mice, CNS Neurol.

Disord. Drug Targets, 20, 298-308, https://doi.org/10.2174/1871527319666201005170659.

131. Shen, K., Mao, Q., Yin, X., Zhang, C., Jin, Y., Deng, A., Gu, Z., and Chen, B. (2018) NLRP3 inflammasome ac-

tivation leads to epileptic neuronal apoptosis, Curr. Neurovasc. Res., 15, 276-281, https://doi.org/10.2174/

1567202616666181122165540.

132. Wang, F., Wang, Y., Zhang, Q.-Y., Hu, K.-Y., Song, Y.-J., Yang, L., Fei, F., Xu, C.-L., Cui, S.-L., Ruan, Y.-P., Wang, Y., and

Chen, Z. (2024) Small-molecule caspase-1 inhibitor CZL80 terminates refractory status epilepticus via inhibition

of glutamatergic transmission, Acta Pharmacol. Sin., 45, 1381-1392, https://doi.org/10.1038/s41401-024-01257-0.

133. Vezzani, A., Aronica, E., Mazarati, A., and Pittman, Q. J. (2013) Epilepsy and brain inflammation, Exp. Neurol.,

244, 11-21, https://doi.org/10.1016/j.expneurol.2011.09.033.

134. Riazi, K., Galic, M. A., Kuzmiski, J. B., Ho, W., Sharkey, K. A., and Pittman, Q. J. (2008) Microglial activation and

TNFα production mediate altered CNS excitability following peripheral inflammation, Proc. Natl. Acad. Sci. USA,

105, 17151-17156, https://doi.org/10.1073/pnas.0806682105.

135. Rodgers, K. M., Hutchinson, M. R., Northcutt, A., Maier, S. F., Watkins, L. R., and Barth, D. S. (2009) The cortical

innate immune response increases local neuronal excitability leading to seizures, Brain, 132, 2478-2486, https://

doi.org/10.1093/brain/awp177.

136. Dyomina, A. V., Zubareva, O. E., Smolensky, I. V., Vasilev, D. S., Zakharova, M. V., Kovalenko, A. A., Schwarz, A. P.,

Ischenko, A. M., and Zaitsev, A. V. (2020) Anakinra reduces epileptogenesis, provides neuroprotection, and at-

tenuates behavioral impairments in rats in the lithium-pilocarpine model of epilepsy, Pharmaceuticals, 13, 340,

https://doi.org/10.3390/ph13110340.

137. Lee, S.-H., Han, S.-H., and Lee, K.-W. (2000) Kainic acid-induced seizures cause neuronal death in infant rats

pretreated with lipopolysaccharide, Neuroreport, 11, 507-510, https://doi.org/10.1097/00001756-200002280-00016.

METABOLIC REPROGRAMMING OF GLIA IN EPILEPTOGENESIS 763

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

138. Suleymanova, E. M. (2021) Behavioral comorbidities of epilepsy and neuroinflammation: evidence from exper-

imental and clinical studies, Epilepsy Behav., 117, 107869, https://doi.org/10.1016/j.yebeh.2021.107869.

139. Aronica, E., Bauer, S., Bozzi, Y., Caleo, M., Dingledine, R., Gorter, J. A., Henshall, D. C., Kaufer, D., Koh, S.,

Löscher, W., Louboutin, J.-P., Mishto, M., Norwood, B. A., Palma, E., Poulter, M. O., Terrone, G., Vezzani, A., and

Kaminski, R. M. (2017) Neuroinflammatory targets and treatments for epilepsy validated in experimental models,

Epilepsia, 58, 27-38, https://doi.org/10.1111/epi.13783.

140. Noe, F. M., Polascheck, N., Frigerio, F., Bankstahl, M., Ravizza, T., Marchini, S., Beltrame, L., Banderó, C. R.,

Löscher, W., and Vezzani, A. (2013) Pharmacological blockade of IL-1β/IL-1 receptor type 1 axis during epilep-

togenesis provides neuroprotection in two rat models of temporal lobe epilepsy, Neurobiol. Dis., 59, 183-193,

https://doi.org/10.1016/j.nbd.2013.07.015.

141. Sharma, R., Leung, W. L., Zamani, A., O’Brien, T. J., Casillas Espinosa, P. M., and Semple, B. D. (2019) Neuroin-

flammation in post-traumatic epilepsy: pathophysiology and tractable therapeutic targets, Brain Sci., 9, 11, https://

doi.org/10.3390/brainsci9110318.

142. Knoblach, S. M., and Faden, A. I. (1998) Interleukin-10 improves outcome and alters proinflammatory cyto-

kine expression after experimental traumatic brain injury, Exp. Neurol., 153, 143-151, https://doi.org/10.1006/

exnr.1998.6877.

143. Levin, S. G., and Godukhin, O. V. (2007) Protective effects of interleukin-10 on the development of epileptiform

activity evoked by transient episodes of hypoxia in rat hippocampal slices, Neurosci. Behav. Physiol., 37, 467-

470, https://doi.org/10.1007/s11055-007-0036-1.

144. Sun, Y., Ma, J., Li, D., Li, P., Zhou, X., Li, Y., He, Z., Qin, L., Liang, L., and Luo, X. (2019) Interleukin-10 inhibits

interleukin-1β production and inflammasome activation of microglia in epileptic seizures, J. Neuroinflammation,

16, 66, https://doi.org/10.1186/s12974-019-1452-1.

145. Radpour, M., Khoshkroodian, B., Asgari, T., Pourbadie, H. G., and Sayyah, M. (2023) Interleukin 4 reduces brain

hyperexcitability after traumatic injury by downregulating TNF-α, upregulating IL-10/TGF-β, and potential di-

recting macrophage/microglia to the M2 anti-inflammatory phenotype, Inflammation, 46, 1810-1831, https://

doi.org/10.1007/s10753-023-01843-0.

146. Herz, J., Fu, Z., Kim, K., Dykstra, T., Wall, M., Li, H., Salvador, A. F., Zou, B., Yan, N., Blackburn, S. M.,

Andrews, P. H., Goldman, D. H., Papadopoulos, Z., Smirnov, I., Xie, X. S., and Kipnis, J. (2021) GABAergic neu-

ronal IL-4R mediates T cell effect on memory, Neuron, 109, 3609-3618, https://doi.org/10.1016/j.neuron.2021.

10.022.

147. Bhattarai, P., Thomas, A. K., Cosacak, M. I., Papadimitriou, C., Mashkaryan, V., Froc, C., Reinhardt, S., Kurth, T.,

Dahl, A., Zhang, Y., and Kizil, C. (2016) IL4/STAT6 signaling activates neural stem cell proliferation and neu-

rogenesis upon amyloid-β42 aggregation in adult zebrafish brain, Cell Rep., 17, 941-948, https://doi.org/

10.1016/j.celrep.2016.09.075.

148. Kastin, A. J., Akerstrom, V., and Pan, W. (2003) Interleukin-10 as a CNS therapeutic: the obstacle of the

blood-brain/blood-spinal cord barrier, Brain Res. Mol. Brain Res., 114, 168-171, https://doi.org/10.1016/S0169-

328X(03)00167-0.

149. Liu, Y., Fang, C., Chen, C., Yu, Y., Wang, J., Ye, L., Zhang, C., and Feng, Z. (2026) Inhibition of the SGLT2/

NHE-1/NLRP3 signaling axis attenuates neuroinflammation and oxidative stress to ameliorate seizures and cog-

nitive impairment in epileptic mice, Free Radic. Biol. Med., 246, 742-759, https://doi.org/10.1016/j.freeradbiomed.

2025.12.059.

150. Meng, X.-F., Tan, L., Tan, M.-S., Jiang, T., Tan, C.-C., Li, M.-M., Wang, H.-F., and Yu, J.-T. (2014) Inhibition of the

NLRP3 inflammasome provides neuroprotection in rats following amygdala kindling-induced status epilepticus,

J. Neuroinflammation, 11, 212, https://doi.org/10.1186/s12974-014-0212-5.

151. Zakharova, M. V., Dyomina, A. V., Kovalenko, A. A., Zubareva, O. E., Ischenko, A. M., and Zaitsev, A. V. (2024)

Anakinra promotes M2 microglia activation during the latent phase of the lithium-pilocarpine model of temporal

lobe epilepsy, J. Evol. Biochem. Physiol., 60, 672-689, https://doi.org/10.1134/S0022093024020182.

152. Auvin, S., Shin, D., Mazarati, A., and Sankar, R. (2010) Inflammation induced by LPS enhances epileptogen-

esis in immature rat and may be partially reversed by IL1RA, Epilepsia, 51, 34-38, https://doi.org/10.1111/

j.1528-1167.2010.02606.x.

153. Marchi, N., Fan, Q., Ghosh, C., Fazio, V., Bertolini, F., Betto, G., Batra, A., Carlton, E., Najm, I., Granata, T., and

Janigro, D. (2009) Antagonism of peripheral inflammation reduces the severity of status epilepticus, Neurobiol.

Dis., 33, 171-181, https://doi.org/10.1016/j.nbd.2008.10.002.

154. Ravizza, T., Noé, F., Zardoni, D., Vaghi, V., Sifringer, M., and Vezzani, A. (2008) Interleukin Converting Enzyme

inhibition impairs kindling epileptogenesis in rats by blocking astrocytic IL-1beta production, Neurobiol. Dis.,

31, 327-333, https://doi.org/10.1016/j.nbd.2008.05.007.

ZAKHAROVA et al.764

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

155. Kunz, T., and Oliw, E. H. (2001) The selective cyclooxygenase-2 inhibitor rofecoxib reduces kainate-induced cell

death in the rat hippocampus, Eur. J. Neurosci., 13, 569-575, https://doi.org/10.1046/j.1460-9568.2001.01420.x.

156. Polascheck, N., Bankstahl, M., and Löscher, W. (2010) The COX-2 inhibitor parecoxib is neuroprotective but

not antiepileptogenic in the pilocarpine model of temporal lobe epilepsy, Exp. Neurol., 224, 219-233, https://

doi.org/10.1016/j.expneurol.2010.03.014.

157. Oliveira, M. S., Furian, A. F., Royes, L. F. F., Fighera, M. R., Fiorenza, N. G., Castelli, M., Machado, P., Bohrer, D.,

Veiga, M., Ferreira, J., Cavalheiro, E. A., and Mello, C. F. (2008) Cyclooxygenase-2/PGE2 pathway facilitates pen-

tylenetetrazol-induced seizures, Epilepsy Res., 79, 14-21, https://doi.org/10.1016/j.eplepsyres.2007.12.008.

158. Li, T., Zhai, X., Jiang, J., Song, X., Han, W., Ma, J., Xie, L., Cheng, L., Chen, H., and Jiang, L. (2017) Intraperi-

toneal injection of IL-4/IFN-γ modulates the proportions of microglial phenotypes and improves epilepsy out-

comes in a pilocarpine model of acquired epilepsy, Brain Res., 1657, 120-129, https://doi.org/10.1016/j.brainres.

2016.12.006.

159. Christian, C. A., Reddy, D. S., Maguire, J., and Forcelli, P. A. (2020) Sex differences in the epilepsies and associ-

ated comorbidities: implications for use and development of pharmacotherapies, Pharmacol. Rev., 72, 767-800,

https://doi.org/10.1124/pr.119.017392.

160. Pizzo, F., Collotta, A. D., Di Nora, A., Costanza, G., Ruggieri, M., and Falsaperla, R. (2022) Ketogenic diet in pe-

diatric seizures: a randomized controlled trial review and meta-analysis, Expert Rev. Neurother., 22, 169-177,

https://doi.org/10.1080/14737175.2022.2030220.

161. Desli, E., Spilioti, M., Evangeliou, A., Styllas, F., Magkos, F., and Dalamaga, M. (2022) The efficacy and safety

of ketogenic diets in drug-resistant epilepsy in children and adolescents: a systematic review of randomized

controlled trials, Curr. Nutr. Rep., 11, 102-116, https://doi.org/10.1007/s13668-022-00405-4.

162. D’Andrea Meira, I., Romão, T. T., Pires do Prado, H. J., Krüger, L. T., Pires, M. E. P., and da Conceição, P. O.

(2019) Ketogenic diet and epilepsy: what we know so far, Front. Neurosci., 13, 5, https://doi.org/10.3389/fnins.

2019.00005.

163. Guerreiro, D., Almeida, A., and Ramalho, R. (2024) Ketogenic diet and neuroinflammation: implications for

neuroimmunometabolism and therapeutic approaches to refractory epilepsy, Nutrients, 16, 23, https://doi.org/

10.3390/nu16233994.

164. Tao, Y., Leng, S. X., and Zhang, H. (2022) Ketogenic diet: an effective treatment approach for neurodegenerative

diseases, Curr. Neuropharmacol., 20, 2303-2319, https://doi.org/10.2174/1570159X20666220830102628.

165. Bough, K.J., Wetherington, J., Hassel, B., Pare, J. F., Gawryluk, J. W., Greene, J. G., Shaw, R., Smith,Y., Geiger, J. D.,

and Dingledine, R. J. (2006) Mitochondrial biogenesis in the anticonvulsant mechanism of the ketogenic diet,

Ann. Neurol., 60, 223-235, https://doi.org/10.1002/ana.20899.

166. Rudy, L., Carmen, R., Daniel, R., Artemio, R., and Moisés, R.-O. (2020) Anticonvulsant mechanisms of the

ketogenic diet and caloric restriction, Epilepsy Res., 168, 106499, https://doi.org/10.1016/j.eplepsyres.2020.

106499.

167. Youm, Y.-H., Nguyen, K. Y., Grant, R. W., Goldberg, E. L., Bodogai, M., Kim, D., D’Agostino, D., Planavsky, N.,

Lupfer, C., Kanneganti, T. D., Kang, S., Horvath, T. L., Fahmy, T. M., Crawford, P. A., Biragyn, A., Alnemri, E., and

Dixit, V. D. (2015) The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory

disease, Nat. Med., 21, 263-269, https://doi.org/10.1038/nm.3804.

168. Sun, W., Wang, Q., Zhang, R., and Zhang, N. (2023) Ketogenic diet attenuates neuroinflammation and induces

conversion of M1 microglia to M2 in an EAE model of multiple sclerosis by regulating the NF-κB/NLRP3 pathway

and inhibiting HDAC3 and P2X7R activation, Food Funct., 14, 7247-7269, https://doi.org/10.1039/D3FO00122A.

169. Shippy, D. C., Wilhelm, C., Viharkumar, P. A., Raife, T. J., and Ulland, T. K. (2020) β-Hydroxybutyrate inhibits

inflammasome activation to attenuate Alzheimer’s disease pathology, J. Neuroinflammation, 17, 280, https://

doi.org/10.1186/s12974-020-01948-5.

170. Guo, M., Wang, X., Zhao, Y., Yang, Q., Ding, H., Dong, Q., Chen, X., and Cui, M. (2018) Ketogenic diet im-

proves brain ischemic tolerance and inhibits NLRP3 inflammasome activation by preventing Drp1-mediated

mitochondrial fission and endoplasmic reticulum stress, Front. Mol. Neurosci., 11, 86, https://doi.org/10.3389/

fnmol.2018.00086.

171. Neudorf, H., and Little, J. P. (2024) Impact of fasting & ketogenic interventions on the NLRP3 inflammasome:

a narrative review, Biomed. J., 47, 100677, https://doi.org/10.1016/j.bj.2023.100677.

172. Si, J., Wang, Y., Xu, J., and Wang, J. (2020) Antiepileptic effects of exogenous β-hydroxybutyrate on kainic acid-

induced epilepsy, Exp. Ther. Med., 20, 177, https://doi.org/10.3892/etm.2020.9307.

173. Simeone, T. A., Matthews, S. A., Samson, K. K., and Simeone, K. A. (2017) Regulation of brain PPARgamma2

contributes to ketogenic diet anti-seizure efficacy, Exp. Neurol., 287, 54-64, https://doi.org/10.1016/j.expneurol.

2016.08.006.

METABOLIC REPROGRAMMING OF GLIA IN EPILEPTOGENESIS 765

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

174. McDaniel, S. S., Rensing, N. R., Thio, L. L., Yamada, K. A., and Wong, M. (2011) The ketogenic diet inhibits

the mammalian target of rapamycin (mTOR) pathway, Epilepsia, 52, e7-e11, https://doi.org/10.1111/j.1528-1167.

2011.02981.x.

175. Milder, J. B., Liang, L.-P., and Patel, M. (2010) Acute oxidative stress and systemic Nrf2 activation by the keto-

genic diet, Neurobiol. Dis., 40, 238-244, https://doi.org/10.1016/j.nbd.2010.05.030.

176. Ziegler, D. R., Ribeiro, L. C., Hagenn, M., Siqueira, I. R., Araújo, E., Torres, I. L. S., Gottfried, C., Netto, C. A., and

Gonçalves, C.-A. (2003) Ketogenic diet increases glutathione peroxidase activity in rat hippocampus, Neurochem.

Res., 28, 1793-1797, https://doi.org/10.1023/A:1026107405399.

177. Milder, J., and Patel, M. (2012) Modulation of oxidative stress and mitochondrial function by the ketogenic diet,

Epilepsy Res., 100, 295-303, https://doi.org/10.1016/j.eplepsyres.2011.09.021.

178. Masino, S. A., Li, T., Theofilas, P., Sandau, U. S., Ruskin, D. N., Fredholm, B. B., Geiger, J. D., Aronica, E., and

Boison, D. (2011) A ketogenic diet suppresses seizures in mice through adenosine A

receptors, J. Clin. Invest.,

121, 2679-2683, https://doi.org/10.1172/JCI57813.

179. Khatami, S. H., Alehossein, P., Ehtiati, S., Zarei, T., Salmani, F., Bagherzadeh, S., Razmafrooz, M., Rajabibazl, M.,

Halimi, A., Shahmohammadi, M. R., Jouibari, M. F., Tafakhori, A., and Karima, S. (2025) Therapeutic efficacy

of intermittent ketogenesis in modulating adenosine metabolism, immune response, and seizure severity in

refractory temporal lobe epilepsy: a pilot human study, Inflammation, 48, 3264-3281, https://doi.org/10.1007/

s10753-025-02264-x.

180. Rho, J. M., Anderson, G. D., Donevan, S. D., and White, H. S. (2002) Acetoacetate, acetone, and dibenzylamine (a

contaminant in l-(+)-beta-hydroxybutyrate) exhibit direct anticonvulsant actions in vivo, Epilepsia, 43, 358-361,

https://doi.org/10.1046/j.1528-1157.2002.47901.x.

181. Kim, D. Y., Simeone, K. A., Simeone, T. A., Pandya, J. D., Wilke, J. C., Ahn, Y., Geddes, J. W., Sullivan, P. G., and

Rho, J. M. (2015) Ketone bodies mediate antiseizure effects through mitochondrial permeability transition, Ann.

Neurol., 78, 77-87, https://doi.org/10.1002/ana.24424.

182. Senn, L., Costa, A.-M., Avallone, R., Socała, K., Wlaź, P., and Biagini, G. (2023) Is the peroxisome proliferator-

activated receptor gamma a putative target for epilepsy treatment? Current evidence and future perspectives,

Pharmacol. Ther., 241, 108316, https://doi.org/10.1016/j.pharmthera.2022.108316.

183. Puligheddu, M., Pillolla, G., Melis, M., Lecca, S., Marrosu, F., De Montis, M. G., Scheggi, S., Carta, G., Murru, E.,

Aroni, S., Muntoni, A. L., and Pistis, M. (2013) PPAR-alpha agonists as novel antiepileptic drugs: preclinical

findings, PLoS One, 8, e64541, https://doi.org/10.1371/journal.pone.0064541.

184. Zubareva, O. E., and Melik-Kasumov, T. B. (2021) The gut-brain axis and peroxisome proliferator-activated

receptors in the regulation of epileptogenesis, J. Evol. Biochem. Physiol., 57, 743-760, https://doi.org/10.1134/

S0022093021040013.

185. Michalik, L., Auwerx, J., Berger, J. P., Chatterjee, V. K., Glass, C. K., Gonzalez, F. J., Grimaldi, P. A., Kadowaki, T.,

Lazar, M. A., O’Rahilly, S., Palmer, C. N. A., Plutzky, J., Reddy, J. K., Spiegelman, B. M., Staels, B., and Wahli, W.

(2006) International Union of Pharmacology. LXI. Peroxisome proliferator-activated receptors, Pharmacol. Rev.,

58, 726-741, https://doi.org/10.1124/pr.58.4.5.

186. Moreno, S., Farioli-Vecchioli, S., and Cerù, M. P. (2004) Immunolocalization of peroxisome proliferator-activat-

ed receptors and retinoid X receptors in the adult rat CNS, Neuroscience, 123, 131-145, https://doi.org/10.1016/

j.neuroscience.2003.08.064.

187. Warden, A., Truitt, J., Merriman, M., Ponomareva, O., Jameson, K., Ferguson, L. B., Mayfield, R. D., and Harris,

R. A. (2016) Localization of PPAR isotypes in the adult mouse and human brain, Sci. Rep., 6, 27618, https://

doi.org/10.1038/srep27618.

188. Adabi Mohazab, R., Javadi-Paydar, M., Delfan, B., and Dehpour, A. R. (2012) Possible involvement of PPAR-gamma

receptor and nitric oxide pathway in the anticonvulsant effect of acute pioglitazone on pentylenetetrazole-in-

duced seizures in mice, Epilepsy Res., 101, 28-35, https://doi.org/10.1016/j.eplepsyres.2012.02.015.

189. Hong, S., Xin, Y., HaiQin, W., GuiLian, Z., Ru, Z., ShuQin, Z., HuQing, W., Li, Y., Ning, B., and YongNan, L. (2013)

The PPARγ agonist rosiglitazone prevents neuronal loss and attenuates development of spontaneous recurrent

seizures through BDNF/TrkB signaling following pilocarpine-induced status epilepticus, Neurochem. Int., 63, 405-

412, https://doi.org/10.1016/j.neuint.2013.07.010.

190. Sun, H., Huang, Y., Yu, X., Li, Y., Yang, J., Li, R., Deng, Y., and Zhao, G. (2008) Peroxisome proliferator-activated

receptor gamma agonist, rosiglitazone, suppresses CD40 expression and attenuates inflammatory responses after

lithium pilocarpine-induced status epilepticus in rats, Int. J. Dev. Neurosci., 26, 505-515, https://doi.org/10.1016/

j.ijdevneu.2008.01.009.

191. Hong, S., Xin, Y., HaiQin, W., GuiLian, Z., Ru, Z., ShuQin, Z., HuQing, W., Li, Y., and Yun, D. (2011) The

PPARγ agonist rosiglitazone prevents cognitive impairment by inhibiting astrocyte activation and oxidative

ZAKHAROVA et al.766

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

stress following pilocarpine-induced status epilepticus, Neurol. Sci., 33, 559-566, https://doi.org/10.1007/s10072-

011-0774-2.

192. Subkhankulov, M. R., Sinyak, D. S., Guk, V. A., Postnikova, T. Yu., Roginskaya, A. I., and Zubareva, O. E. (2024)

The effect of cardarine on the challenges of histopaotological and behavioral phenomena in the lithium-pilo-

carpine model of temporal lobe epilepsy in rats [in Russian], Ross. Physiol. Zhurn. im. I. M. Sechenov, 110,

137-155, https://doi.org/10.31857/S0869813924010096.

193. Kovalenko, A. A., Zakharova, M. V., Zubareva, O. E., Schwarz, A. P., Skorik, Y. A., and Zaitsev, A. V. (2025)

Fenofibrate as a PPARα agonist modulates neuroinflammation and glutamate receptors in a rat model of tem-

poral lobe epilepsy: region-specific effects and behavioral outcomes, Int. J. Mol. Sci., 26, 18, https://doi.org/

10.3390/ijms26189054.

194. Gómez-Eguílaz, M., Ramón-Trapero, J. L., Pérez-Martínez, L., and Blanco, J. R. (2018) The beneficial effect of

probiotics as a supplementary treatment in drug-resistant epilepsy: a pilot study, Benef. Microbes, 9, 875-881,

https://doi.org/10.3920/BM2018.0018.

195. Zubareva, O. E., Dyomina, A. V., Kovalenko, A. A., Roginskaya, A. I., Melik-Kasumov, T. B., Korneeva, M. A.,

Chuprina, A. V., Zhabinskaya, A. A., Kolyhan, S. A., Zakharova, M. V., Gryaznova, M. O., and Zaitsev, A. V. (2023)

Beneficial effects of probiotic bifidobacterium longum in a lithium-pilocarpine model of temporal lobe epilepsy

in rats, Int. J. Mol. Sci., 24, 8451, https://doi.org/10.3390/ijms24098451.

196. Engel, J. J., Kuhl, D. E., Phelps, M. E., Rausch, R., and Nuwer, M. (1983) Local cerebral metabolism during partial

seizures, Neurology, 33, 400-413, https://doi.org/10.1212/WNL.33.4.400.

197. Dello Russo, C., Gavrilyuk, V., Weinberg, G., Almeida, A., Bolanos, J. P., Palmer, J., Pelligrino, D., Galea, E., and

Feinstein, D. L. (2003) Peroxisome proliferator-activated receptor gamma thiazolidinedione agonists increase

glucose metabolism in astrocytes, J. Biol. Chem., 278, 5828-5836, https://doi.org/10.1074/jbc.M208132200.

198. Tanaka, Y., Minami, Y., and Endo, M. (2023) Ror1 promotes PPARα-mediated fatty acid metabolism in astrocytes,

Genes Cells, 28, 307-318, https://doi.org/10.1111/gtc.13013.

199. Purnell, B. S., Alves, M., and Boison, D. (2023) Astrocyte-neuron circuits in epilepsy, Neurobiol. Dis., 179, 106058,

https://doi.org/10.1016/j.nbd.2023.106058.

200. Yu, X., Shao, X. G., Sun, H., Li, Y. N., Yang, J., Deng, Y. C., and Huang, Y. G. (2008) Activation of cerebral per-

oxisome proliferator-activated receptors gamma exerts neuroprotection by inhibiting oxidative stress following

pilocarpine-induced status epilepticus, Brain Res., 1200, 146-158, https://doi.org/10.1016/j.brainres.2008.01.047.

201. Villapol, S. (2018) Roles of peroxisome proliferator-activated receptor gamma on brain and peripheral inflam-

mation, Cell. Mol. Neurobiol., 38, 121-132, https://doi.org/10.1007/s10571-017-0554-5.

202. Esmaeili, M. A., Yadav, S., Gupta, R. K., Waggoner, G. R., Deloach, A., Calingasan, N. Y., Beal, M. F., and Kiaei, M.

(2016) Preferential PPAR-α activation reduces neuroinflammation, and blocks neurodegeneration in  vivo, Hum.

Mol. Genet., 25, 317-327, https://doi.org/10.1093/hmg/ddv477.

203. Polak, P. E., Kalinin, S., Dello Russo, C., Gavrilyuk, V., Sharp, A., Peters, J. M., Richardson, T. A., Willson, T. M.,

Weinberg, G., and Feinstein, D. L. (2005) Protective effects of a peroxisome proliferator-activated receptor-beta/

delta agonist in experimental autoimmune encephalomyelitis, J. Neuroimmunol., 168, 65-75, https://doi.org/10.1016/

j.jneuroim.2005.07.006.

204. Ji, H., Wang, H., Zhang, F., Li, X., Xiang, L., and Aiguo, S. (2010) PPARγ agonist pioglitazone inhibits microglia

inflammation by blocking p38 mitogen-activated protein kinase signaling pathways, Inflamm. Res., 59, 921-929,

https://doi.org/10.1007/s00011-010-0203-7.

205. Xu, J., Chavis, J. A., Racke, M. K., and Drew, P. D. (2006) Peroxisome proliferator-activated receptor-alpha and

retinoid X receptor agonists inhibit inflammatory responses of astrocytes, J. Neuroimmunol., 176, 95-105, https://

doi.org/10.1016/j.jneuroim.2006.04.019.

206. Fang, M., Yu, Q., Ou, J., Lou, J., Zhu, J., and Lin, Z. (2024) The neuroprotective mechanisms of PPAR-γ: inhibition

of microglia-mediated neuroinflammation and oxidative stress in a neonatal mouse model of hypoxic-ischemic

white matter injury, CNS Neurosci. Ther., 30, e70081, https://doi.org/10.1111/cns.70081.

207. Ding, Y., Wang, Y., Qi, M., Zhang, X., and Wu, D. (2025) Pioglitazone modulates microglia M1/M2 polarization

through PPAR-γ pathway and exerts neuroprotective effects in experimental subarachnoid hemorrhage, Mol.

Neurobiol., 62, 5930-5946, https://doi.org/10.1007/s12035-024-04664-w.

208. Zhao, Q., Wu, X., Yan, S., Xie, X., Fan, Y., Zhang, J., Peng, C., and You, Z. (2016) The antidepressant-like effects of

pioglitazone in a chronic mild stress mouse model are associated with PPARγ-mediated alteration of microglial

activation phenotypes, J. Neuroinflammation, 13, 259, https://doi.org/10.1186/s12974-016-0728-y.

209. Ramanan, S., Kooshki, M., Zhao, W., Hsu, F.-C., and Robbins, M. E. (2008) PPARalpha ligands inhibit radiation-

induced microglial inflammatory responses by negatively regulating NF-kappaB and AP-1 pathways, Free Radic.

Biol. Med., 45, 1695-1704, https://doi.org/10.1016/j.freeradbiomed.2008.09.002.

METABOLIC REPROGRAMMING OF GLIA IN EPILEPTOGENESIS 767

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

210. Deng, Y., Jiang, X., Deng, X., Chen, H., Xu, J., Zhang, Z., Liu, G., Yong, Z., Yuan, C., Sun, X., and Wang, C.

(2020) Pioglitazone ameliorates neuronal damage after traumatic brain injury via the PPARγ/NF-κB/IL-6 signaling

pathway, Genes Dis., 7, 253-265, https://doi.org/10.1016/j.gendis.2019.05.002.

211. Schnegg, C. I., Kooshki, M., Hsu, F.-C., Sui, G., and Robbins, M. E. (2012) PPARδ prevents radiation-induced proin-

flammatory responses in microglia via transrepression of NF-κB and inhibition of the PKCα/MEK1/2/ERK1/2/AP-1

pathway, Free Radic. Biol. Med., 52, 1734-1743, https://doi.org/10.1016/j.freeradbiomed.2012.02.032.

212. Stienstra, R., Mandard, S., Tan, N. S., Wahli, W., Trautwein, C., Richardson, T. A., Lichtenauer-Kaligis, E.,

Kersten, S., and Müller, M. (2007) The interleukin-1 receptor antagonist is a direct target gene of PPARalpha in

liver, J. Hepatol., 46, 869-877, https://doi.org/10.1016/j.jhep.2006.11.019.

213. Zubareva, O.E., Kharisova, A. R., Roginskaya, A.I., Kovalenko, A.A., Zakharova, M.V., Schwarz, A.P., Sinyak,D.S.,

and Zaitsev, A. V. (2024) PPARβ/δ agonist GW0742 modulates microglial and astroglial gene expression in a rat

model of temporal lobe epilepsy, Int. J. Mol. Sci., 25, 10015, https://doi.org/10.3390/ijms251810015.

214. Meier, J. J. (2012) GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus, Nat. Rev.

Endocrinol., 8, 728-742, https://doi.org/10.1038/nrendo.2012.140.

215. Gulyaeva, N. V. (2025) Glucagon-like peptide-1 receptor agonists are promising for the treatment of brain dis-

eases: an outlook from the perspective of integrative physiology, J. Evol. Biochem. Phys., 61, 1326-1348, https://

doi.org/10.1134/S0022093025050023.

216. Liu, Q. K. (2024) Mechanisms of action and therapeutic applications of GLP-1 and dual GIP/GLP-1 receptor ag-

onists, Front. Endocrinol., 15, 1431292, https://doi.org/10.3389/fendo.2024.1431292.

217. Jones, B. (2022) The therapeutic potential of GLP-1 receptor biased agonism, Br. J. Pharmacol., 179, 492-510,

https://doi.org/10.1111/bph.15497.

218. Drucker, D. J. (2006) The biology of incretin hormones, Cell Metab., 3, 153-165, https://doi.org/10.1016/j.cmet.

2006.01.004.

219. Wen, Y., Wu, K., Xie,Y., Dan, W., Zhan, Y., and Shi, Q. (2019) Inhibitory effects of glucagon-like peptide-1 receptor

on epilepsy, Biochem. Biophys. Res. Commun., 511, 79-86, https://doi.org/10.1016/j.bbrc.2019.02.028.

220. Zhao, Y., Li, T., Zhang, L., Yang, J., Zhao, F., Wang, Y., Ouyang, Y., and Liu, J. (2024) TRAF6 promotes spi-

nal microglial M1 polarization to aggravate neuropathic pain by activating the c-JUN/NF-kB signaling pathway,

Cell Biol. Toxicol., 40, 54, https://doi.org/10.1007/s10565-024-09900-6.

221. Zhai, Y., Lu, K., Yuan, Y., Zhang, Z., Xue, L., Zhao, F., Xu, X., and Wang, H. (2025) Semaglutide improves cognitive

function and neuroinflammation in APP/PS1 transgenic mice by activating AMPK and inhibiting TLR4/NF-κB

pathway, J. Alzheimers. Dis., 105, 416-432, https://doi.org/10.1177/13872877251329439.

222. Lv, R., Zhao, Y., Wang, X., He, Y., Dong, N., Min, X., Liu, X., Yu, Q., Yuan, K., Yue, H., and Yin, Q. (2024) GLP-1

analogue liraglutide attenuates CIH-induced cognitive deficits by inhibiting oxidative stress, neuroinflammation,

and apoptosis via the Nrf2/HO-1 and MAPK/NF-κB signaling pathways, Int. Immunopharmacol., 142, 113222,

https://doi.org/10.1016/j.intimp.2024.113222.

223. Wang, L., Ding, J., Zhu, C., Guo, B., Yang, W., He, W., Li, X., Wang, Y., Li, W., Wang, F., and Sun, T. (2021) Semaglu-

tide attenuates seizure severity and ameliorates cognitive dysfunction by blocking the NLR family pyrin domain

containing 3 inflammasome in pentylenetetrazole-kindled mice, Int. J. Mol. Med., 48, 219, https://doi.org/10.3892/

ijmm.2021.5052.

224. Wang, Z.-J., Han, W.-N., Chai, S.-F., Li, Y., Fu, C.-J., Wang, C.-F., Cai, H.-Y., Li, X.-Y., Wang, X., Hölscher, C., and

Wu, M.-N. (2024) Semaglutide promotes the transition of microglia from M1 to M2 type to reduce brain inflam-

mation in APP/PS1/tau mice, Neuroscience, 563, 222-234, https://doi.org/10.1016/j.neuroscience.2024.11.022.

225. Obydah, W., Abouelnaga, A. F., Abass, M., Saad, S., Yehia, A., Ammar, O. A.-A., Badawy, A. M., Ibrahim, M. M.,

and Hussein, A. M. (2023) Possible role of oxidative stress and Nrf2/HO-1 pathway in pentylenetetrazole-induced

epilepsy in aged rats, Reports Biochem. Mol. Biol., 12, 147-158, https://doi.org/10.61186/rbmb.12.1.147.

226. An, F.-M., Chen, S., Xu, Z., Yin, L., Wang, Y., Liu, A.-R., Yao, W.-B., and Gao, X.-D. (2015) Glucagon-like peptide-1

regulates mitochondrial biogenesis and tau phosphorylation against advanced glycation end product-induced

neuronal insult: Studies in vivo and in vitro, Neuroscience, 300, 75-84, https://doi.org/10.1016/j.neuroscience.

2015.05.023.

227. Antmen, F. M., Fedaioglu, Z., Acar, D., Sayar, A. K., Yavuz, I. E., Ada, E., Karakose, B., Rzayeva, L., Demircan, S.,

Kardouh, F., Senay, S., Kolgazi, M., Suyen, G., and Oz-Arslan, D. (2024) Exploring liraglutide in lithium-pilo-

carpine-induced temporal lobe epilepsy model in rats: impact on inflammation, mitochondrial function, and

behavior, Biomedicines, 12, 10, https://doi.org/10.3390/biomedicines12102205.

228. Erdogan, M.A., Erdogan, A., and Erbas, O. (2023) The anti-seizure effect of liraglutide on Ptz-induced convulsions

through its anti-oxidant and anti-inflammatory properties, Neurochem. Res., 48, 188-195, https://doi.org/10.1007/

s11064-022-03736-4.

ZAKHAROVA et al.768

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

229. Xu, X., Gao, W., Li, L., Hao, J., Yang, B., Wang, T., Li, L., Bai, X., Li, F., Ren, H., Zhang, M., Zhang, L., Wang, J.,

Wang, D., Zhang, J., and Jiao, L. (2021) Annexin A1 protects against cerebral ischemia-reperfusion injury by

modulating microglia/macrophage polarization via FPR2/ALX-dependent AMPK-mTOR pathway, J. Neuroinflam-

mation, 18, 119, https://doi.org/10.1186/s12974-021-02174-3.

230. Jung, B.-K., Park, Y., Yoon, B., Bae, J.-S., Han, S.-W., Heo, J.-E., Kim, D.-E., and Ryu, K.-Y. (2023) Reduced se-

cretion of LCN2 (lipocalin 2) from reactive astrocytes through autophagic and proteasomal regulation alle-

viates inflammatory stress and neuronal damage, Autophagy, 19, 2296-2317, https://doi.org/10.1080/15548627.

2023.2180202.

231. Deng, Y., Duan, R., Ding, W., Gu, Q., Liu, M., Zhou, J., Sun, J., and Zhu, J. (2022) Astrocyte-derived exosomal

nicotinamide phosphoribosyltransferase (Nampt) ameliorates ischemic stroke injury by targeting AMPK/mTOR

signaling to induce autophagy, Cell Death Dis., 13, 1057, https://doi.org/10.1038/s41419-022-05454-9.

232. Mehrabi,S., Sanadgol,N., Barati,M., Shahbazi,A., Vahabzadeh,G., Barzroudi,M., Seifi,M., Gholipourmalekabadi,M.,

and Golab, F. (2018) Evaluation of metformin effects in the chronic phase of spontaneous seizures in pilocarpine

model of temporal lobe epilepsy, Metab. Brain Dis., 33, 107-114, https://doi.org/10.1007/s11011-017-0132-z.

233. Bojja, S. L., Anand, S., Minz, R. W., and Medhi, B. (2024) Metformin alleviates reactive gliosis and neurode-

generation, improving cognitive deficit in a rat model of temporal lobe epilepsy, Brain Res., 1844, 149138,

https://doi.org/10.1016/j.brainres.2024.149138.

234. Yang, Y., Zhu, B., Zheng, F., Li, Y., Zhang, Y., Hu, Y., and Wang, X. (2017) Chronic metformin treatment facilitates

seizure termination, Biochem. Biophys. Res. Commun., 484, 450-455, https://doi.org/10.1016/j.bbrc.2017.01.157.

235. Çetindağ Çiltaş, A., Şahin, B., and Hacisüleyman, L. (2026) Metformin attenuates PTZ-Induced seizures and cog-

nitive impairment and is associated with altered NOS/NO signaling: combined in  vivo and in  silico evidence,

Neurol. Res., https://doi.org/10.1080/01616412.2025.2611012.

236. Zhao, W., Xie, C., Zhang, X., Liu, J., Liu, J., and Xia, Z. (2023) Advances in the mTOR signaling pathway and its

inhibitor rapamycin in epilepsy, Brain Behav., 13, e2995, https://doi.org/10.1002/brb3.2995.

237. Li, C., Cai, Y., Chen, Y., Tong, J., Li, Y., Liu, D., Wang, Y., Li, Z., Wang, Y., and Li, Q. (2024) ABCG2 shields against

epilepsy, relieves oxidative stress and apoptosis via inhibiting the ISGylation of STAT1 and mTOR, Redox Biol.,

75, 103262, https://doi.org/10.1016/j.redox.2024.103262.

238. Huang, H., Cui, G., Tang, H., Kong, L., Wang, X., Cui, C., Xiao, Q., and Ji, H. (2019) Silencing of microRNA-146a

alleviates the neural damage in temporal lobe epilepsy by down-regulating Notch-1, Mol. Brain, 12, 102, https://

doi.org/10.1186/s13041-019-0523-7.

239. Wang, L., Song, L.-F., Chen, X.-Y., Ma, Y.-L., Suo, J.-F., Shi, J.-H., and Chen, G.-H. (2019) MiR-181b inhibits P38/JNK

signaling pathway to attenuate autophagy and apoptosis in juvenile rats with kainic acid-induced epilepsy via

targeting TLR4, CNS Neurosci. Ther., 25, 112-122, https://doi.org/10.1111/cns.12991.

240. Xiaoying, G., Guo, M., Jie, L., Yanmei, Z., Ying, C., Shengjie, S., Haiyan, G., Feixiang, S., Sihua, Q., and Jiahang, S.

(2020) CircHivep2 contributes to microglia activation and inflammation via miR-181a-5p/SOCS2 signalling in mice

with kainic acid-induced epileptic seizures, J. Cell. Mol. Med., 24, 12980-12993, https://doi.org/10.1111/jcmm.15894.

241. Han, C.-L., Liu, Y.-P., Guo, C.-J., Du, T.-T., Jiang, Y., Wang, K.-L., Shao, X.-Q., Meng, F.-G., and Zhang, J.-G. (2020)

The lncRNA H19 binding to let-7b promotes hippocampal glial cell activation and epileptic seizures by targeting

Stat3 in a rat model of temporal lobe epilepsy, Cell Prolif., 53, e12856, https://doi.org/10.1111/cpr.12856.

242. Amorim, R.P., Araújo, M.G.L., Valero,J., Lopes-Cendes,I., Pascoal, V.D.B., Malva, J.O., and da Silva Fernandes,M.J.

(2017) Silencing of P2X7R by RNA interference in the hippocampus can attenuate morphological and behav-

ioral impact of pilocarpine-induced epilepsy, Purinergic Signal., 13, 467-478, https://doi.org/10.1007/s11302-

017-9573-4.

243. Zhang, Y., Zhang, M., Zhu, W., Pan, X., Wang, Q., Gao, X., Wang, C., Zhang, X., Liu, Y., Li, S., and Sun, H. (2020)

Role of elevated thrombospondin-1 in kainic acid-induced status epilepticus, Neurosci. Bull., 36, 263-276, https://

doi.org/10.1007/s12264-019-00437-x.

244. Sun, H., Ma, L., Zhang, Y., Pan, X., Wang, C., Zhang, J., Zhang, X., Sun, H., Wang, Q., and Zhu, W. (2018) A

purinergic P2 receptor family-mediated increase in thrombospondin-1 bolsters synaptic density and epileptic

seizure activity in the amygdala-kindling rat model, Front. Cell. Neurosci., 12, 302, https://doi.org/10.3389/fncel.

2018.00302.

245. Geng, C., Ren, X., Cao, P., Chu, X., Wei, P., Liu, Q., Lu, Y., Fu, B., Li, W., Li, Y., and Zhao, G. (2024) Macrophage

membrane–biomimetic nanoparticles target inflammatory microenvironment for epilepsy treatment, Theranos-

tics, 14, 6652-6670, https://doi.org/10.7150/thno.99260.

246. Zhao, Y., Chen, F., Chen, C., Yang, Y., Wang, L., Zhu, J., Wang, X., Liu, Y., and Ding, J. (2025) Coordination

acid-engineered Prussian Blue affects glycometabolic reprogramming in microglia for epileptic treatment,

J. Nanobiotechnology, 23, 436, https://doi.org/10.1186/s12951-025-03408-9.

METABOLIC REPROGRAMMING OF GLIA IN EPILEPTOGENESIS 769

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

247. Yuan, X., Fu, Z., Ji, P., Guo, L., Al-Ghamdy, A. O., Alkandiri, A., Habotta, O. A., Abdel Moneim, A. E., and

Kassab, R. B. (2020) Selenium nanoparticles pre-treatment reverse behavioral, oxidative damage, neuronal loss

and neurochemical alterations in pentylenetetrazole-induced epileptic seizures in mice, Int. J. Nanomedicine, 15,

6339-6353, https://doi.org/10.2147/IJN.S259134.

248. Al Omairi, N. E., Albrakati, A., Alsharif, K. F., Almalki, A. S., Alsanie, W., Abd Elmageed, Z. Y., Zaafar, D.,

Lokman, M. S., Bauomy, A. A., Belal, S. K., Abdel-Daim, M. M., Alyami, H., and Kassab, R. B. (2022) Selenium

nanoparticles with prodigiosin rescue hippocampal damage associated with epileptic seizures induced by pen-

tylenetetrazole in rats, Biology, 11, 3, https://doi.org/10.3390/biology11030354.

249. Mohamed, K. M., Abdelfattah, M. S., El, M., Megrin, W. A. A., Fehaid, A., Kassab, R. B., and Moneim, A. E. A.

(2023) Rutin-loaded selenium nanoparticles modulated the redox status, inflammatory, and apoptotic path-

ways associated with pentylenetetrazole-induced epilepsy in mice, Green Process. Synth., 12, 20230010, https://

doi.org/10.1515/gps-2023-0010.

250. El-Missiry, M. A., Othman, A. I., Amer, M. A., Sedki, M., Ali, S. M., and El-Sherbiny, I. M. (2020) Nanoformulat-

ed ellagic acid ameliorates pentylenetetrazol-induced experimental epileptic seizures by modulating oxidative

stress, inflammatory cytokines and apoptosis in the brains of male mice, Metab. Brain Dis., 35, 385-399, https://

doi.org/10.1007/s11011-019-00502-4.

251. Saha, L., Kumari, P., Rawat, K., Gautam, V., Sandhu, A., Singh, N., Bhatia, A., Bhattacharya, S., Sinha, V. R., and

Chakrabarti, A. (2023) Neuroprotective effect of berberine nanoparticles against seizures in pentylenetetrazole

induced kindling model of epileptogenesis: role of anti-oxidative, anti-inflammatory, and anti-apoptotic mecha-

nisms, Neurochem. Res., 48, 3055-3072, https://doi.org/10.1007/s11064-023-03967-z.

252. Jalili, C., Gholami, M., and Kakebaraei, S. (2024) Protective effect of crocin-loaded nanoparticles in rats fol-

lowing epileptic seizures: biochemical, behavioral and histopathological outcomes, Heliyon, 10, e36122, https://

doi.org/10.1016/j.heliyon.2024.e36122.

Publisher’s Note. Pleiades Publishing remains neutral with regard to jurisdictional claims in published

maps and institutional affiliations. AI tools may have been used in the translation or editing of this article.