Effect of the PPARγ Agonist Pioglitazone on Rat Behavior and Expression of Epileptogenesis-Related Genes during the Latent Phase of the Lithium-Pilocarpine Model

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Adeliya R. Kharisova^1#, Olga E. Zubareva^1,a*#, Anna A. Kovalenko¹, Denis S. Sinyak¹, and Aleksey V. Zaitsev¹

¹Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, 194223 Saint Petersburg, Russia

^* To whom correspondence should be addressed.

^# These authors contributed equally to the work.

Received: February 2, 2026; Revised: April 22, 2026; Accepted: April 24, 2026

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Epilepsy is a severe chronic condition that remains pharmacoresistant in approximately 30% of the patients, which necessitates the search for new treatment approaches. Epileptogenesis involves disruption in the interaction between metabolic pathways and neuronal signaling. A promising therapeutic target is the peroxisome proliferator-activated receptors (PPARs), which integrate metabolic and anti-inflammatory signals. The aim of this work was to evaluate effects of the PPARγ agonist pioglitazone on the complex of epileptogenesis manifestations: behavior and expression of the genes encoding glial markers, cytokines, neurotrophic factors, and glutamate receptor subunits during the latent phase of the lithium-pilocarpine model in rats. The study was conducted with 8-week-old male Wistar rats divided into control and experimental groups. Pioglitazone was administered at low doses (7 mg/kg after status epilepticus, followed by 1 mg/kg/day for 7 days). On the days 8-9, locomotor and social activities were assessed using the Open Field and Social Interaction tests. On the day 10, expression of the genes encoding markers for activation and various states of astro- and microglia, cytokines, neurotrophic factors, and glutamate receptor subunits was analyzed in the dorsal hippocampus and temporal cortex using RT-qPCR. It was shown that pioglitazone partially alleviated the pilocarpine-induced social deficit. In the brain of rats with the epilepsy model, increased expression of the glial activation markers (Gfap, Aif1) and cytokines (Il1b, Il1rn) was found, which was weakly affected by administration of pioglitazone. At the same time, the drug completely prevented the pilocarpine-induced decrease in the expression of the glutamate receptor subunit gene Grin2b. The obtained data suggest that, at the applied doses, pioglitazone primarily modulates expression of the genes related to synaptic plasticity and does not exert a significant effect on expression of the genes associated with glial activation and inflammation. Thus, activation of PPARγ as a metabolic sensor during epileptogenesis could stabilize transcriptional programs that are important for maintaining synaptic homeostasis, which opens the possibilities for targeted modulation of metabolic pathways in epilepsy therapy.

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KEY WORDS: pioglitazone, PPARγ, temporal lobe epilepsy, lithium-pilocarpine model, astroglia, microglia, gene expression, neuroinflammation, glutamate receptors, behavior

DOI: 10.1134/S0006297926600183

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