Article

ISSN 0006-2979, Biochemistry (Moscow), 2026, Vol. 91, No. 6, pp. 1034-1049 © Pleiades Publishing, Ltd., 2026.

1034

Environmental Enrichment May Mitigate

Dexamethasone-Induced Changes

in the Glycemic Curve

Ludmila P. Filaretova

1,a

*, Olga Yu. Morozova

, Polina V. Punina

Olga P. Komkova

, Tatiana T. Podvigina

, and Natalia I. Yarushkina

I. P. Pavlov Institute of Physiology, Russian Academy of Sciences,

199034 St. Petersburg, Russia

e-mail: filaretovalp@infran.ru

Received March 30, 2026

Revised June 15, 2026

Accepted June 15, 2026

Abstract— Previously, we demonstrated that administration of dexamethasone (Dex) at a dose of 1  mg/kg,

24  h before an ulcerogenic stimulus exerts a pro-ulcerogenic effect, accompanied by disturbances in car-

bohydrate metabolism. In the present study, we examined the influence of housing conditions – standard

conditions  (SC), social isolation  (SI), and environmental enrichment  (EE) conditions – on the Dex-induced

changes in carbohydrate metabolism, as well as on hematological parameters. Experiments were conducted

with male rats during the winter period. Starting from the age of 30 days, the animals were housed for

6  weeks under SC, SI, or EE conditions. Dex (1  mg/kg, intraperitoneal) or its vehicle (control) was admin-

istered 24  h prior to the glucose tolerance test (GTT), after which food was removed. Following the GTT,

indomethacin (IM) was administered at an ulcerogenic dose; 4  h later, the rats were decapitated, and blood

samples were collected to assess corticosterone levels and hematological parameters, including calculation of

the neutrophil-to-lymphocyte ratio (NLR). Alongside the IM administration experiment, a control experiment

including vehicle administration was performed according to the same protocol, in which the vehicle of

IM was administered instead of IM itself. Administration of glucose during the GTT led to the increase in

the blood glucose levels, reaching maximum (peak) at 30 min in all control, previously fasted animals (SC,

SI, EE groups). Beginning at 60  min, the glucose levels gradually declined in all control groups, returning

to the baseline only in the control rats from the EE  group. In the rats maintained under SC conditions,

pretreatment with Dex resulted in the reduction in the peak of the glycemic curve, accompanied by the

corresponding decrease in the area under the curve (AUC) and reduced rate of decline in the blood glu-

cose levels compared with the respective control group. In the rats housed under EE condition, resistance

to the effects of Dex was observed, as evidenced by the absence of changes in the glycemic curve peak,

AUC, or rate of decline in the blood glucose levels relative to the corresponding control group. The control

rats from the SI group exhibited lower values of the glycemic curve peak, AUC, and rate of decline in

the blood glucose levels than the rats from the SC and EE groups. Administration of Dex did not produce

any further changes in these parameters. Dex administration induced a marked increase in the NLR in all

groups (SC, SI, and EE), both in the rats treated with IM and in the animals receiving its vehicle. Taken

together, these findings indicate that a single administration of Dex (1  mg/kg; 24  h after injection) to the rats

from the SC group could alter glycemic response and increase NLR. Housing under EE conditions prevents

the Dex-induced changes in the glycemic curve.

DOI: 10.1134/S0006297926601000

Keywords: dexamethasone, pro-ulcerogenic effect, glucose tolerance, glucose tolerance test, glycemic curve,

neutrophil-to-lymphocyte ratio, environmental enrichment, social isolation, rats

* To whom correspondence should be addressed.

ENVIRONMENTAL ENRICHMENT, DEXAMETHASONE, AND GLYCEMIC CURVE 1035

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 6 2026

INTRODUCTION

Contribution of the interaction between the

neural signals and metabolic pathways to the brain

functioning cannot be limited to consideration of this

interaction at the brain level alone. The whole-organ-

ism level, which is the focus of integrative physiolo-

gy  [1-3], is necessary for this. A review of the recent

publications indicates a renewed interest among the

researchers in the problem of brain–body interac-

tion  [4-7], which is now considered broader than the

brain–gut axis interaction, which was first brilliantly

demonstrated by I.  P.  Pavlov  [8,  9]. Nevertheless, the

study of the brain–gastrointestinal tract (brain–GI)

axis, with its bidirectional interaction between the

brain and the GI tract as a multicomponent system

including neural, hormonal, metabolic, and immune

pathways, remains one of the most intensively devel-

oping areas [10-14].

Glucocorticoid hormones, which are produced in

the final link of the hypothalamic–pituitary–adreno-

cortical system (HPA axis, a key hormonal stress sys-

tem [15,  16] and hormonal component of the brain–

GI axis  [17]) represent one of the important factors

in the regulation of glucose homeostasis, the main

energy source for the brain. Temporary increase in

the blood glucose levels is important for ensuring

maximum brain activity. This is achieved through

stimulating effect of the hormones on gluconeogen-

esis, inhibitory effect on the glucose uptake and uti-

lization in skeletal muscles and white adipose tissue,

tissue-specific effect on the glycogen metabolism, and

modulating effect on the secretion of insulin and glu-

cagon from the pancreas [16, 18-20].

Our interest in the issue of the influence of glu-

cocorticoid hormones on carbohydrate metabolism is

related to elucidation of the mechanisms of the gas-

troprotective effect of glucocorticoid hormones pro-

duced during stress, which has been discovered in

our previous studies [21-24]. This allowed us to revise

the traditional view of these hormones as ulcerogenic

factors and of the HPA axis as an ulcerogenic com-

ponent of the brain–GI axis. According to our results,

acute stress-induced activation of the HPA axis is a

gastroprotective component of the brain–GI axis  [17,

25,  26]. Under certain conditions, a gastroprotective

effect was also demonstrated in our studies for the

exogenous glucocorticoid hormones  [27,  28], which

indicates the possibility of their dual effects: phys-

iological gastroprotective effect identified in our

studies and the known pathological pro-ulcerogenic

effect.

To study the mechanisms of transformation of

the physiological gastroprotective action of gluco-

corticoid hormones into pathological pro-ulcerogenic

consequences, we developed experimental models in

rats using these hormones, including dexamethasone

(Dex), in which we observed such transformation

[27,  28]. The dexamethasone model demonstrates

that a single administration of Dex at the same dose

of 1  mg/kg could lead to both gastroprotective and

pro-ulcerogenic effects, depending on the duration of

the hormone’s action. When the hormone was admin-

istered 1-3  h before an ulcerogenic stimulus, a gastro-

protective effect was observed; the effect was absent

when the hormone was administered 12  h before an

ulcerogenic stimulus; administration of the hormone

24  h before the stimulus resulted in the early mani-

festation of a pro-ulcerogenic effect. In studying the

mechanisms, we showed that the Dex-induced short-

term support of the blood glucose levels in the fasted

rats contributes to its gastroprotective effect, but the

prolonged maintenance of blood glucose levels leads

to disorders of carbohydrate metabolism, including

development of insulin resistance, which, togeth-

er with the Dex-induced inhibition of the HPA axis,

contributes to realization of the pro-ulcerogenic effect

of Dex.

The present study was aimed at further investi-

gation of the mechanisms of pro-ulcerogenic action

of Dex associated with the disorders of carbohydrate

metabolism and searching for approaches to reduce

magnitude of these disorders. In addition to the dis-

orders of carbohydrate metabolism, therapy with

glucocorticoid hormones could lead to the changes

in the leukocyte composition of blood: neutrophilia

and lymphopenia with corresponding increase in the

neutrophil-to-lymphocyte ratio (NLR)  [29-32], increase

in which has also been shown in hyperglycemia  [33].

In connection with these effects and our interest in

an integrative approach, in our experimental model,

we studied the effect of Dex on the leukocyte com-

position of blood.

The available literature data  [34-37] and the re-

sults of our previous studies  [38,  39] indicate pre-

ventive potential of the environmental enrichment

against the development of various pathological dis-

orders. Environmental enrichment, which combines

increased physical activity, cognitive and sensory

stimulation, and social interaction, is considered an

effective non-drug strategy [37, 38, 40]. This served

as the basis for us to test whether the environmental

enrichment could be considered as an approach to

reduce the Dex-induced changes in carbohydrate me-

tabolism, as well as possible changes in the leukocyte

composition of blood, which characterizes immune

properties of the organism. Social isolation (a hous-

ing condition opposite to environmental enrichment)

which often leads to exacerbation of the pathological

changes in the body  [38,  39], was of interest to us as

a comparison with the influence of environmental

enrichment.

FILARETOVA et al.1036

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 6 2026

The objective of this work was to study prolonged

(24  h) action of Dex, which exerts a pro-ulcerogenic

effect on the stomach, on the glucose tolerance, as

well as on the neutrophil-to-lymphocyte ratio, and

dependence of the identified effects of Dex on the

housing conditions of rats: standard conditions, social

isolation, and environmental enrichment.

MATERIALS AND METHODS

Animal housing conditions. Experiments were

conducted with male Sprague-Dawley rats from the

Shared Research Facility “Biocollection of the IP RAS”

(Koltushi, Leningrad Region) during the winter sea-

son. Animals were kept in the laboratory vivarium

at a temperature of 21-22°C and a 12  h  :  12  h light/

dark regime (lights on at 8:00, off at 20:00). Rat pups

at 30  days of age (weight 90  ±  1.2  g, n  =  144) were

immediately after weaning randomly distributed into

groups with different housing conditions: standard

conditions  (SC), social isolation  (SI), or environmental

enrichment  (EE).

SI conditions involved housing of animals in-

dividually in standard opaque plastic rat cages

(54×38×20  cm) without physical or visual contact

with other rats. In EE conditions, rats were housed in

groups of 6 in large wire cages (100×50×80  cm) with

various “enriching” accessories: a running wheel, hid-

ing houses, shelves, ladders, tubes, hammocks, water

baths, and toys. The set of accessories was changed

three times a week, except for the running wheel,

which was constantly available. Control for the SI and

EE groups were rats housed in standard opaque plas-

tic cages (54×38×20  cm) in groups of 6 (SC). Rats were

housed under SC, SI, and EE conditions for 6  weeks.

Throughout this period, body weight of the rats was

assessed weekly, which in all groups increased uni-

formly and reached on average 355  ±  3.5  g (n  =  144)

after 6  weeks, with no differences found between the

groups (SC, SI, and EE).

Experimental design. After 6  weeks of housing

animals under SC, SI, and EE conditions (Fig.  1), on

the first day of the experiment (Day  1), half of the

rats in each group were administered Dex (1  mg/kg,

intraperitoneal, Sigma-Aldrich, Germany), and the

other half were administered its vehicle (propylene

glycol, 1  mL/kg body weight, Vecton, Russia) (Table  1).

Immediately after injection, food was removed for

24  h (fasting). On the next day (Day  2), 24  h after

administration of Dex or its vehicle (control) and

start of fasting, a glucose tolerance test (GTT) was

performed. After completion of the GTT, rats in each

group (which remained fasted) were administered

indomethacin at an ulcerogenic dose (IM, 35  mg/kg,

subcutaneously, GLPBIO, Korea). According to the

same protocol (Fig.  1), a separate control experiment

was conducted in which, instead of IM, its vehicle

(physiological saline, 5  mL/kg body weight with addi-

tion of a drop of Tween  80, Rosmedbio, Russia) was

administered. Four hours after the injection of IM or

its vehicle, the rats were decapitated. After decapita-

tion, thymus was extracted to assess its relative mass,

and blood was collected from the trunk vessels to as-

sess corticosterone levels, blood glucose levels, and

hematological parameters.

Glucose tolerance assessment: GTT. To assess

glucose tolerance in the GTT, blood glucose levels

were determined in the previously fasted (24  h) rats

before glucose administration (0  point, baseline level)

and after glucose administration (2  g/kg, intraperito-

neal) at 30, 60, 120, and 180  min (Fig.  1). Blood glu-

cose levels were measured using test strips and a

glucometer (Accu-Chek Performa, Germany) in a drop

of blood taken from the tail vein (after incision) at

the tip of the tail. Based on the test results, glycemic

Fig.  1. Experimental design. Rat pups at 30 days of age were placed for 6  weeks in different housing conditions: standard

conditions (SC), social isolation (SI), or environmental enrichment (EE) conditions. After 6  weeks, rats in each group were

administered dexamethasone (Dex) or its vehicle, and food was immediately removed for 24  h (Day  1). On the next day

(Day  2), 24  h after administration of Dex or its vehicle and start of fasting, a glucose tolerance test (GTT) was performed.

Immediately after completion of the GTT, rats in each group were administered indomethacin (IM) at an ulcerogenic dose.

Four hours after injection, the animals were decapitated. A  control experiment was conducted according to the same pro-

tocol, in which the vehicle of IM was administered instead of  IM.

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Table 1. Drug administration protocol and number of

rats in groups

Housing

conditions

Group Drugs

SC,

n = 46

1 Dex + IM,

n = 11

2 Vehicle of Dex + IM,

n = 11

3 Dex + Vehicle of IM,

n = 12

4 Vehicle of Dex + Vehicle of IM,

n = 12

SI,

n = 48

1 Dex + IM,

n = 12

2 Vehicle of Dex + IM,

n = 12

3 Dex + Vehicle of IM,

n = 12

4 Vehicle of Dex + Vehicle of IM,

n = 12

EE,

n = 48

1 Dex + IM,

n = 12

2 Vehicle of Dex + IM,

n = 12

3 Dex + Vehicle of IM,

n = 12

4 Vehicle of Dex + Vehicle of IM,

n = 12

Note. SC – standard conditions; SI– social isolation; EE– en-

vironmental enrichment; Dex – dexamethasone; IM – indo-

methacin; n – number of rats in the group. Groups of rats

that received the vehicle of IM (control experiment) are

marked in bold.

curves were plotted. In addition to the dynamics of

blood glucose levels and maximum increase in the

blood glucose levels (glycemic curve peak) after glu-

cose load, the rate of decline in blood glucose lev-

els and incremental area under the glycemic curve

(iAUC) were evaluated. iAUC was calculated using

the trapezoidal method [41, 42] with the formula:

((C1

  +  C2)/2 − Cbas)  ×  (T2 − T1), where Cbas is blood

glucose content at 0 time (baseline level); C1, C2 are

the blood glucose content at adjacent time points

T1 and T2, respectively. Calculation of the rate of

decline in blood glucose levels was performed in

the interval from 30 to 180  min using the formula:

(C180  −  C30)/(T180  −  T30), where C30 and C180 are

the blood glucose content at 30 and 180  min, respec-

tively; T180 and T30 are time points after glucose

administration.

Hematological parameters and corticosterone

content in blood. Blood analysis was performed

using an automated hematology analyzer BC-30 Vet

(Shenzhen Mindray Bio-Medical Electronics Co. Ltd,

China), which includes determination of qualitative

and quantitative composition of blood. Blood was

collected in EDTA K3 tubes to prevent clotting. Be-

fore measurement, the blood was diluted with a sol-

vent for measuring small-volume samples. In this

study, we were interested in leukocyte composition

parameters of the blood, which characterize immune

properties of the organism: granulocytes (neutrophils)

and lymphocytes, were analyzed. Based on the ob-

tained data, the neutrophil-to-lymphocyte ratio (NLR)

was calculated: total number of granulocytes (neutro-

phils)/total number of lymphocytes.

Corticosterone levels in blood plasma were de-

termined using an enzyme-linked immunosorbent as-

say (ELISA) using a “Rat/Mouse Corticosterone ELISA

Kit” (HEMA, Russia) with a Star Fax 2100 analyzer

(Awareness Technology, Inc., USA).

Statistical analysis. Data are presented as a

mean  ±  standard error of the mean (SEM). The re-

search results were analyzed using MedCalc Ver-

sion 12.2.1.0. (Statistics for Biomedical Research,

MedCalc Software, Belgium). All obtained data were

tested for normality (Kolmogorov–Smirnov test).

The Levene’s test was used to assess equality of vari-

ances. Based on the test results, to assess differences

between time points belonging to the same glycemic

curve, the non-parametric Friedman test was used for

comparing repeated measurements. To assess differ-

ences between two glycemic curves at a given time

point, the Mann–Whitney U  test for two independent

groups was used. In other cases, to assess differences

between the groups, the Kruskal–Wallis test with sub-

sequent post  hoc test was applied. Outliers (extreme

values far beyond the sample) were identified and

excluded based on the results of three tests: Grubbs

test, Generalized ESD test, Tukey test. Differences

between the groups were considered significant at

p  <  0.05.

RESULTS

Effect of a single administration of Dex on glu-

cose metabolism parameters in the GTT in rats de-

pending on their housing conditions. In the control

rats (with Dex vehicle injected), housed under SC, SI,

and EE conditions, blood glucose levels before the glu-

cose load (baseline level, 0 point), after fasting (24 h),

FILARETOVA et al.1038

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 6 2026

did not differ between each other and were

4.7  ±  0.09  mmol/L (n  =  11); 4.8  ±  0.16 mmol/L (n  =  12);

4.8  ±  0.06  mmol/L (n  =  12), respectively. In all control

groups, administration of glucose led to the increase

in the blood glucose levels, which was maximal at

30  min (glycemic curve peak) (Fig.  2,  a-c), with the

peak of the glycemic curve in the rats from the SI

group being lower (p  <  0.05) compared to the peaks

in the rats from the SC and EE groups, which did

not differ from each other (Fig.  2d). After reaching

the peak, the blood glucose levels in all groups (SC,

SI, EE) gradually decreased: glucose levels at 60  min

were significantly lower (p  <  0.05) compared to the

levels at 30  min, but higher (p  <  0.05) compared to

the levels at 180  min (Fig.  2,  a-c). However, the rate of

decline in the blood glucose levels differed between

the groups: in the rats from EE group, the rate of

decline in blood glucose levels in the interval from 30

to 180min was higher (p  <  0.05) compared to the rats

from the SI group (Fig.  2e). It should be emphasized

that only in the rats housed under EE conditions

did the blood glucose level after glucose load fully

recover, as evidenced by the absence of differences

between the blood glucose levels at 180  min and the

baseline level at 0 point (Fig.  2c).

Administration of Dex 24  h prior to the GTT, on

the background of fasting, itself (i.e., in the absence

of other exposures) caused increase in the blood

glucose levels (0  point, baseline level) in all groups

(Fig.  2,  a-c), with no significant differences found be-

tween the Dex-induced baseline blood glucose levels

in the rats housed under SC, SI, and EE conditions.

In all groups, the peak of the glycemic curve after

Dex administration, as well as after administration of

its vehicle, was observed at 30  min, but its magnitude

varied. In the rats housed under SC conditions, reduc-

tion in the peak of the glycemic curve was observed

compared to the peak in the control rats receiving

the Dex vehicle. At the same time, Dex had no ef-

fect on the magnitude of the peaks of the glycemic

curves in the rats from the EE and SI groups, which

did not differ from the corresponding values in the

control rats injected with the Dex vehicle (Fig.  2,a-d).

The magnitude of the glycemic curve peak in the EE

group after Dex administration was higher (p  <  0.05)

compared to that in the SC group (Fig.  2d), while the

peak values in the SI and SC groups did not differ.

Dex administration affected not only magnitude

of the glycemic curve peaks but also the rate of de-

cline in the blood glucose levels (Fig.  2e). In the SI

and EE groups, the rate of decline in the blood glu-

cose levels was higher compared to that in the SC

group: in the SI and EE groups, decrease (p  <  0.05) in

the glucose levels compared to 30  min was observed

starting from 60  min (Fig.  2, b and c), whereas in the

rats from the SC group, the glucose level at 60  min

still did not differ from the level at 30  min, and only

at 120  min did the glucose level in this group became

lower (p  <  0.05) compared to 30 and 60  min (Fig.  2a).

Dex administration significantly reduced the rate of

decline in the blood glucose levels in the interval

from 30 to 180  min in the rats from the SC group but

did not change the rate of decline in the rats from

the SI and EE groups compared to the corresponding

values in the control animals (Fig.  2e). After Dex ad-

ministration, the rate of decline in the blood glucose

levels in the EE group (p  <  0.05) remained higher

compared to the SC and SI groups (Fig.  2e) and did

not change compared to the corresponding value in

the control rats.

Although the blood glucose levels in all groups

(SC, SI, and EE) gradually decreased after the glu-

cose load, the Dex-induced glucose levels at 120 and

180  min remained elevated compared to the corre-

sponding values in the control rats injected with the

Dex vehicle (Fig.  2,  a-c).

Comparison of the areas under the glycemic

curves (iAUC) (Fig.  2e) revealed a smaller area under

the curve in the control rats (injected with Dex ve-

hicle) from the SI group compared to the areas in

the curves from the rats from the SC and EE groups,

which did not differ from each other. Dex adminis-

tration led to the significant reduction in the area

under the curve in the rats from SC group but had

no effect on the corresponding curve parameter from

the rats from the SI and EE groups. The area under

the curve from the rats from the EE group was sig-

nificantly higher than that from the rats from the SC

group, both after administration of Dex and its vehi-

cle (Fig.  2e).

Thus, comparison of the glycemic curves revealed

differences between the SC, SI, and EE groups. The

control rats (injected with Dex vehicle) from the SI

group differed from the rats in the SC and EE groups

in having lower values of the glycemic curve peak,

rate of decline in the blood glucose levels, and area

under the curve. At the same time, Dex administra-

tion did not lead to further changes in these values.

Dex administration led to the significant changes in

the glycemic curve (reduction in the glycemic curve

peak, rate of decline in blood glucose levels, and area

under the curve) in the rats from the SC group com-

pared to the corresponding values in the control rats

(injected with Dex vehicle). In the rats housed un-

der EE conditions, full recovery of the blood glucose

levels after glucose load was observed in the control

rats (injected with Dex vehicle) as well as resistance

to the action of Dex: absence of changes in the gly-

cemic curve peak, rate of decline in the blood glu-

cose levels, and area under the curve compared to

the corresponding values in the control rats (injected

with Dex vehicle).

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BIOCHEMISTRY (MOSCOW) Vol. 91 No. 6 2026

Fig.  2. Effect of a single administration of dexamethasone (Dex, 1  mg/kg, 24  h before testing in combination with 24-h

fasting) on glycemic curves in the glucose tolerance test (GTT) in the rats depending on their housing conditions. Glycemic

curves in the GTT in the rats housed under SC  (a), SI  (b), and EE  (c) conditions; maximum blood glucose level (peak) at

30  min  (d), rate of decline in the blood glucose levels in the interval from 30 to 180  min  (e), and incremental area under

the glycemic curves (iAUC)  (f). Curves: 1)  Dex vehicle; 2)  Dex. SC – standard conditions; SI – social isolation; EE – environ-

mental enrichment. Significance of differences at the level of p  <  0.05: a-c) *  relative to the corresponding baseline level

(0  point on the given curve); +  relative to 30  min on the given curve; #  relative to the group “Dex vehicle” at the given

time point; d-f)*  relative to the group “SC  +  Dex vehicle”; #  relative to the EE group. Number of rats in the group  (n)  11-12.

FILARETOVA et al.1040

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 6 2026

Fig.  3. Effect of single administration of dexamethasone (Dex, 1  mg/kg, 24  h before testing in combination with 24-h fasting)

on hematological parameters 4  h after administration of indomethacin (IM) (a-c) or IM vehicle (d-f) in the rats depending

on their housing conditions. Neutrophil-to-lymphocyte ratio, NLR (a and d); percentage of granulocytes (neutrophils) in the

total volume of leukocytes (b and e); percentage of lymphocytes in the total volume of leukocytes (c and f) after admin-

istration of IM or its vehicle. SC – standard conditions; SI – social isolation; EE – environmental enrichment. Significance

of differences at the level of p  <  0.05: *  relative to the corresponding group injected with Dex vehicle; #  relative to the EE

group; +  relative to the SC group. Number of rats in the group  (n)  12.

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BIOCHEMISTRY (MOSCOW) Vol. 91 No. 6 2026

Fig.  4. Effect of single administration of dexamethasone (Dex, 1  mg/kg, 24  h before testing in combination with 24-h fasting)

on blood glucose and corticosterone levels, and relative thymus weight 4  h after administration of indomethacin (IM)(a-c)

or IM vehicle (d-f) in the rats depending on their housing conditions. SC – standard conditions; SI – social isolation;

EE – environmental enrichment. Significance of differences at the level of p  <  0.05: *  relative to the correspond-

ing group injected with Dex vehicle; #  relative to the EE group; +  relative to the SC group. Number of rats in the

group  (n)  12.

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BIOCHEMISTRY (MOSCOW) Vol. 91 No. 6 2026

Effect of a single administration of Dex on

hematological parameters after administration of

IM and its vehicle in the rats depending on their

housing conditions. In the control rats (injected with

Dex vehicle), 4  h after IM administration, the NLR in

the EE group was lower compared to that in the SI

and SC groups (Fig.  3a), which corresponded to the

lower percentage of granulocytes (Fig.  3b) and higher

percentage of lymphocytes in the rats from the EE

group compared to the corresponding indicators in

the rats from SI and SC groups (Fig.  3c). After Dex

administration, sharp increase in the NLR was ob-

served in all groups (SC, SI, EE) (Fig.  3a), which was

accompanied by the increase in the percentage of

granulocytes (Fig.  3b) and decrease in the percentage

of lymphocytes (Fig.  3c) compared to these indicators

in the control rats. It should be emphasized that the

rats from the EE group showed greater resistance to

the action of Dex compared to the rats from the SI

group (Fig.  3a), as evidenced by the lower NLR and

higher percentage of lymphocytes in the rats injected

with Dex from EE group compared to the rats from

the SI group (Fig.  3c).

In the rats that received IM vehicle instead of IM,

in all groups (SC, SI, EE), after Dex administration, a

sharp increase in the NLR was also observed, which

was accompanied by the corresponding changes in

the percentage of lymphocytes and granulocytes; and

the differences between the EE and SI groups identi-

fied after IM administration were also observed.

The control rats (injected with Dex vehicle) from

the EE group had lower NLR, higher percentage of

granulocytes, and lower percentage of lymphocytes

compared to the rats from the SI group. At the same

time, in this case, these indicators did not differ

from the corresponding indicators of the rats from

the SC group (Fig.  3,  d-f). Administration of the IM

vehicle (instead of IM) to the control rats revealed

that housing under SI conditions itself could lead to

the increase in NLR, accompanied by the decrease in

the percentage of lymphocytes and increase in the

percentage of granulocytes (Fig.  3,  d-f). After Dex ad-

ministration increase in the NLR (Fig.  3f), increase in

the percentage of granulocytes (Fig.  3d), and decrease

in the percentage of lymphocytes (Fig.  3e) were ob-

served in all groups (SC, SI, EE), with percentage of

lymphocytes in the rats from the EE group remaining

higher compared to that in the rats from the SI and

SC groups.

Thus, reproduction of the effects of Dex that

were obtained after IM administration in the rats af-

ter administration of its vehicle indicates that they

were caused by the influence of Dex, and not IM.

Single administration of Dex caused sharp increase in

the NLR in all groups of rats (SC, SI, EE). At the same

time, the rats from the EE group showed greater re-

sistance to the action of Dex compared to the rats

from the SI group: in the rats from the SI group, this

indicator was significantly higher than that in the

rats from the EE group. A higher NLR was also found

in the control rats (injected with Dex vehicle) from

the SI group after administration of the IM vehicle.

Effect of a single administration of Dex on

blood glucose and corticosterone levels, thymus

weight in the rats after administration of IM and

its vehicle depending on their housing conditions.

In the control rats (injected with Dex vehicle), 4  h

after IM administration, blood glucose levels in the

rats from the SI group were higher compared to the

levels in the rats from the SC and EE groups, which

did not differ from each other (Fig.  4a). Corticoste-

rone levels and relative thymus weight 4  h after IM

administration did not differ between the rats from

the SC, SI, and EE groups (Fig.  4, b  and  c). Dex ad-

ministration led to the increase in the blood glucose

levels (Fig.  4a), decrease in the blood corticosterone

levels (Fig.  4b), and reduction in the relative thymus

weight (Fig.  4c), with no differences found in these

indicators between the rats from the SC, SI, and EE

groups.

Similar effects were observed 4  h after adminis-

tration of the IM vehicle: in the control rats (injected

with Dex vehicle), SI itself led to the higher blood

glucose levels compared to the SC and EE groups,

which did not differ from each other (Fig.  4d), and

Dex administration also led to the increase in blood

glucose levels (Fig.  4g), decrease in the corticosterone

levels (Fig.  4e), and reduction in the relative thymus

weight (Fig.  4f).

At the same time, after administration of the

IM vehicle, effects were identified that were not

observed after IM administration. That is, 4  h after

administration of the IM vehicle, in the control rats

(injected with Dex vehicle) from different groups (SC,

SI, and EE), differences were found not only between

the blood glucose levels but also between the corti-

costerone levels (Fig.  4e): the rats housed under SI

conditions had higher corticosterone level compared

to the rats from the EE and SC groups (Fig.  4e). Addi-

tionally, administration of the IM vehicle showed that

housing under SI conditions not only itself increases

blood glucose levels but also contributes to the great-

er Dex-induced increase in the blood glucose levels

compared to the SC and EE groups (Fig.  4f), which

did not differ from each other.

Thus, matching of the main effects of Dex (in-

creased blood glucose levels and decreased corticos-

terone levels in the blood, reduced thymus weight)

obtained in the rats with IM administration and in

the rats after administration of the IM vehicle in-

dicates that they were caused by the effect of Dex.

Although in the experiments with IM administration,

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BIOCHEMISTRY (MOSCOW) Vol. 91 No. 6 2026

no dependence of these effects of Dex on the housing

conditions of rats (SC, SI, EE) was revealed, neverthe-

less, in the experiments with administration of the IM

vehicle, a higher blood glucose level was detected in

the rats from the SI group. Higher levels of glucose

and corticosterone in the blood were also found in

the rats from the SI group after administration of the

Dex vehicle.

DISCUSSION

Due to their powerful anti-inflammatory and

immunomodulatory effects, glucocorticoid hormones

are often used to treat inflammatory and autoim-

mune diseases. However, chronic exposure to these

hormones during therapy causes undesirable side ef-

fects, including hyperglycemia and insulin resistance

[19,  20]. The synthetic glucocorticoid hormone Dex,

widely used in clinical practice, is known for its par-

ticularly pronounced negative effects on carbohydrate

metabolism  [43]. In the experimental studies, multi-

ple administrations of Dex are used to model diabe-

tes [44]. The main feature of our work was studying

of the early stages of manifestation of the Dex effects

on carbohydrate metabolism after its single adminis-

tration, in combination with its pro-ulcerogenic ac-

tion, which has been demonstrated in our previous

studies  [27,  28].

According to the main result of this work, the pro-

longed (24  h) action of Dex after its single administra-

tion at a dose of 1  mg/kg, which exerts a pro-ulcero-

genic effect on the stomach, could lead to the changes

in the glycemic curve in rats, while prior housing of

rats under EE conditions could correct these changes.

Increase in the baseline of the blood glucose

levels in the fasted rats after Dex administration

(Fig.  2) that was identified in this study agrees well

with the results of our previous works  [27,  28] and

demonstrates the ability of glucocorticoid hormones

to maintain blood glucose levels  [20]. In this study,

we showed that this effect is manifested regardless

of the housing conditions of the rats: SC, SI, EE. Cat-

abolic effects of Dex demonstrated in our experiment

suggest stimulating effect of Dex on gluconeogenesis

in this case.

Comparative analysis of the glycemic curves ob-

tained in the GTT in the rats from the SC group with

administration of Dex or its vehicle indicates that

the changes in tolerance to the administered glucose

could occur 24  h after single administration of Dex

(1  mg/kg). The Dex-induced decrease in the rate of de-

cline in the blood glucose levels in the rats reflects

existence of a delay in the recovery of the blood glu-

cose levels after glucose load in these animals and

indicates impaired glucose tolerance (Fig.  2). The ob-

served decrease in the rate of glucose decline is con-

sistent with the increase in insulin resistance that

was identified in our previous study in this same

Dex model (1  mg/kg, after 24  h)  [45]. Slowdown in

the recovery of blood glucose levels in the GTT after

Dex administration was also observed in other stud-

ies, but after multiple administrations of Dex  [46,  47].

An unexpected finding is reduction in the peak

of the glycemic curve in the control rats (from the

SC group) 24  h after Dex administration, with cor-

responding decrease in the area under the curve

(Fig.  2). This distinguishes our data from the results

of the studies with multiple Dex administrations, in

which either increase in the peak or no changes were

shown  [46-48]. Possibly, the detected decrease in the

glycemic curve peak is a feature of the early stages

of Dex action. It is difficult to unambiguously inter-

pret this result with a non-standard glycemic curve.

Non-standard nature of the glycemic curve in the rats

from the SC group after Dex administration (Fig.  2a)

is manifested in the fact that, on the one hand, there

is a decrease in the peak that entails decrease in the

area under the curve, which could be interpreted as

an improvement in glucose tolerance, and, on the oth-

er hand, there is a decrease in the rate of decline in

the blood glucose level, which does not agree with

the interpretation of improved glucose tolerance. It is

also important to take into account possible inhibito-

ry effect of Dex on absorption of exogenous glucose

into the blood, which could be the cause of the peak

decrease, since Dex affects glucose transporters  [49].

This possibility is supported by the data obtained in

our previous study on the decrease in glucose absorp-

tion in the intestine 24  h after administration of Dex

at the same dose of 1  mg/kg (unpublished data, co-au-

thors A.  A.  Gruzdkov and L.  V.  Gromova, Pavlov Insti-

tute of Physiology,  RAS). Further research is needed to

clarify the cause of this effect, as well as dependence

of its manifestation on the seasons of the year.

Epidemiological studies indicate that housing

rats under SI conditions increases the risk of devel-

oping diabetes. In the animal experimental studies,

disorders of glucose homeostasis have been detected:

impaired glucose tolerance and reduced insulin sen-

sitivity  [50]. In this study, it was found that housing

rats under SI conditions is accompanied by the de-

crease in the peak of the glycemic curve in the GTT

with corresponding decrease in the area under the

curve, which could be interpreted as improvement

in glucose tolerance under these conditions, and de-

crease in the rate of decline in the blood glucose lev-

els, which does not fit well with this interpretation

(Fig.  2). It turns out that housing under SI conditions

itself led to the changes in the glycemic curve similar

to those observed after Dex administration in the rats

from the SC group. It could be assumed that this is

FILARETOVA et al.1044

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 6 2026

a consequence of the prolonged action of corticoste-

rone, whose production increases under conditions of

chronic stress in the animals housed under SI condi-

tions  [51], which was also shown in this work. Dex

administration to the rats from the SI group did not

have a significant effect on the studied parameters of

the glycemic curve compared to those in the control

rats injected with the Dex vehicle.

The key task of this work was to test the pos-

sibility of correcting the Dex-induced disorders or

changes in carbohydrate metabolism through prior

housing of animals under EE conditions. Preventive

and therapeutic potential of housing animals under

EE conditions has been shown in relation to various

pathological disorders, primarily associated with the

brain functioning [34-37, 40].

Researchers actively continue to consider the

EE-type housing as an effective approach for reduc-

ing anxiety and depression, as well as for improving

memory and learning ability  [52-54]. This non-drug

approach has been also used to eliminate negative

consequences of SI housing  [54]. Effectiveness of EE

housing is also confirmed by the results of our previ-

ous studies, which differ from other works by using

an integrative approach aimed at studying function-

ing of the whole organism. According to our results,

housing rats under EE conditions increases HPA axis

stress reactivity  [39] and work capacity  [38], positively

affects overall functioning of the organism, and could

neutralize negative consequences of the SI housing on

the gastric ulceration  [38]. In this work, we continued

to study preventive potential of the EE housing.

EE housing increased resistance of the rats to

the Dex-induced changes in glycemic curve. This was

manifested in the stability of all studied parameters

(Fig.  2). When reviewing the literature, we found only

one publication devoted to studying of the effect of EE

housing on the Dex-induced disorders of glucose tol-

erance  [48]. In this work, performed with adult male

mice, impaired glucose tolerance in the GTT was de-

tected 21-day after administration of Dex at the dose

of 4  mg/kg, but housing mice under EE conditions

(4  weeks) did not affect the Dex-induced impairment

of the glucose tolerance, despite the identified posi-

tive effects on other metabolic parameters  [48].

According to the experimental design (Fig.  1), the

GTT was performed before the ulcerogenic exposure,

i.e., the results obtained in this case demonstrate

background of the state of carbohydrate metabo-

lism on which the ulcerogenic stimulus was applied:

administration of IM (35  mg/kg on the background

of fasting), which could affect the degree of IM-in-

duced ulceration. Use of the indomethacin ulcero-

genic model in this work and our previous studies

[27, 38, 55-57] is due to the clinical interests in con-

nection with ulcerogenic side effects of nonsteroidal

anti-inflammatory drugs on the gastrointestinal tract

[58]. Previously, in this same indomethacin model, we

demonstrated pro-ulcerogenic effects of Dex (with its

single administration at a dose of 1  mg/kg)  [27,  59];

mechanisms of these effects, as well as approaches to

their reduction, were studied in this work.

Unlike glycemic curves, other parameters (NLR

indicators, blood corticosterone levels, repeated blood

glucose levels, thymus weight) were evaluated after

ulcerogenic exposure (4  h after IM administration)

or control administration of the IM vehicle. It cannot

be completely ruled out that the GTT procedure had

some influence on the listed parameters, which we

plan to check in the subsequent studies. Nevertheless,

in this work, the results of our previous experiments

without prior GTT procedure were confirmed [27,

28]: the Dex-induced increase in the blood glucose

levels, inhibition of corticosterone production, thy-

mus involution, which reflect catabolic effect of the

hormone (Fig.  4). The results of experiments with ad-

ministration of the IM vehicle (instead of IM) allowed

us to conclude that the observed effects were caused

by the action of Dex itself. According to the results

of this work, housing rats under SI conditions could

lead to exacerbation of the Dex-induced increase in

the blood glucose levels, as well as to the higher lev-

els of corticosterone and glucose in the blood in the

control rats injected with the Dex vehicle (Fig.  4).

In studying the mechanisms of pro-ulcerogenic

action of Dex, we gradually introduce new possible

targets of the hormone’s action in our pro-ulcerogenic

model to understand holistic picture of what happens

in the body in this case. In this work, a new target

for us (leukocyte composition of blood) was chosen,

since it is known that therapy with glucocorticoid

hormones could lead to its change [29-32]. Glucocor-

ticoid hormones contribute to neutrophilia by moving

neutrophils into the circulating pool, inhibiting neu-

trophil migration into tissues, and enhancing their

release from the bone marrow. Simultaneously, these

hormones could lead to lymphopenia through acting

on T-lymphocytes by removing them from circulation,

limiting their release from lymphoid tissue, and trig-

gering apoptotic pathways  [60].

A new result obtained in the study of the mech-

anisms of pro-ulcerogenic action of Dex in our ex-

perimental model is the Dex-induced change in the

leukocyte composition of blood: neutrophilia and

lymphopenia with corresponding increase in NLR,

which was detected both in the experiments with IM

administration and in the experiments with inject-

ing its vehicle (Fig.  3). The Dex-induced lymphopenia

is consistent with the identified thymus involution.

Increase in the NLR after Dex administration is con-

sistent with the literature data on the effect of gluco-

corticoid hormones, including Dex, on this parameter

ENVIRONMENTAL ENRICHMENT, DEXAMETHASONE, AND GLYCEMIC CURVE 1045

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 6 2026

[29-32, 60]. It should be noted that we detected this

effect after a single administration of Dex.

The NLR assessment is actively used in clinical

practice as an easily accessible prognostic marker of

systemic inflammation and a tool for determining the

risk of development and complications of various dis-

eases  [61]. High NLR is considered a risk factor for

an unfavorable outcome of diseases [30, 62-65], and

could also be an important indicator in conditions of

disrupted glucose homeostasis  [33]. Since glucocorti-

coid hormones, often used as therapy in the treatment

of many diseases, themselves lead to the increase in

NLR [29-32], it is extremely important in clinical and

veterinary practice to distinguish transient changes in

the NLR caused by the hormones from the changes

arising from the underlying pathologies  [60]. These

facts reinforce relevance of our study. We clarified

that in our case, increase in the NLR was caused

by the influence of Dex.

In this work, the possibility of using EE housing

as an approach to reduce pathological influence of

Dex on the leukocyte composition of blood was test-

ed. Although we did not identify a significant effect

of EE housing on the Dex-induced changes in the NLR

and associated parameters, nevertheless, a positive

effect of EE housing on these parameters was detect-

ed in the control rats injected with the Dex vehicle

(Fig.  3). Rats from the EE group demonstrated great-

er resistance to the action of Dex compared to the

rats from the SI group, in which maximal NLR values

were detected (Fig.  3), indicating more pronounced

disorders of the leukocyte composition of blood.

CONCLUSION

Single administration of Dex (1  mg/kg) 24  h be-

fore the GTT to the previously fasted rats could lead

to the changes in the glycemic curve (reduction in

the curve peak, decrease in the area under the curve,

and reduction in the rate of decline in blood glucose

levels compared to the control), which are difficult

to interpret unambiguously, since the changes indi-

cate both improved and impaired glucose tolerance.

The EE housing could correct the Dex-induced chang-

es in the glycemic curve by promoting resistance to

the action of Dex. Housing rats under SI conditions

itself could lead to the reduction in the peak of the

glycemic curve, decrease in the area under the curve,

and reduction in the rate of decline in the blood glu-

cose levels compared to the corresponding values in

the control rats from the SC and EE groups. At the

same time, Dex administration did not lead to further

changes in these values. A single administration of

Dex could cause a marked increase in the NLR in all

groups: SC, SI, EE. The obtained results, indicating the

effects of Dex on glycemic curves and NLR after only

its single administration, emphasize sensitivity of the

organism to the action of Dex. Housing rats under EE

conditions could prevent negative effects of a single

administration of Dex on the glycemic curve.

Abbreviations

AUC area under the curve

Dex dexamethasone

EE environmental enrichment

GTT glucose tolerance test

HPA hypothalamic–pituitary–adrenocortical

IM indomethacin

NLR neutrophil-to-lymphocyte ratio

SC standard conditions

SI social isolation

Acknowledgments

The authors express their gratitude to the senior lab-

oratory assistants of the Laboratory of Experimental

Endocrinology of the I.  P.  Pavlov Institute of Physi-

ology, Russian Academy of Sciences T.  I.  Kolbasova

and T.  I.  Kritsko and to the engineers Yu.  M.  Punin

and L.  A.  Afanasyeva for their participation in con-

ducting experiments and preparing animals for the

experiments.

Contributions

L.  P.  Filaretova: concept of the work; L.  P.  Filaretova

and N.  I.  Yarushkina: planning of experiments and su-

pervision of the work; O.  Yu.  Morozova, P.  V.  Punina,

O.  P.  Komkova, and N.  I.  Yarushkina: conducting exper-

iments; N.  I.  Yarushkina and O.  Yu.  Morozova: process-

ing of the results and preparation of figures; L.  P.  Filar-

etova, N.  I.  Yarushkina, and T.  T.  Podvigina: discussion

of the results, writing, and editing of the text.

Funding

This work was financially supported by the funds from

the federal budget within the framework of the state

assignment of the I. P. Pavlov Institute of Physiology,

Russian Academy of Sciences (PTNI no.1021062411784-

3-3.1.8, Reg. no. NIOKTR 124020100111-7).

Ethics approval and consent to participate

All experiments were conducted in compliance with

ethical standards approved by the legal acts of the

Russian Federation, the principles of the Basel Decla-

ration, and the recommendations of the Commission

on the Care and Use of Animals of the I.  P.  Pavlov

Institute of Physiology, RAS (Protocol No.  12/09 dated

December 9, 2024).

Conflict of interest

The authors of this work declare that they have no

conflicts of interest.

FILARETOVA et al.1046

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 6 2026

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