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Study of the effect of metformin in small doses on the behavioral characteristics and biochemical parameters of rats

https://doi.org/10.33380/2305-2066-2026-15-2-2186

Abstract

Introduction. Metformin is an oral antidiabetic drug with a known efficacy and safety profile. Currently, there is more data on the effect of metformin on central nervous system functions in small doses, not associated with hypoglycemic effects to influence the aging process and concomitant age-related diseases. However, there is insufficient information about the effect of metformin on the behavioral characteristics and cognitive functions of a healthy body.

Aim. Investigation of the effect of metformin in small doses on behavioral characteristics and some biochemical parameters of blood serum (glucose, cholesterol, and low-density lipoprotein (LDL) levels) in rats.

Materials and methods. The study was performed on 72 male rats weighing 200–250 g of the Wistar line. Behavioral testing was performed after 30 days of metformin administration at doses of 35 and 70 mg/kg. The «T-maze test» installation was used to study the effects on learning and memory processes, and the «Water maze test» was used to study spatial memory. The «Elevated plus-maze test» and «Extrapolation escape task» settings were used to assess the effect of metformin on anxiety in rats. «The Rotarod» complex was used to assess the effect on the physical activity of rats. The biochemical parameters of rat blood serum were measured using an automatic DIRUI CS-300B biochemical analyzer.

Results and discussion. It was found that 30-day administration of metformin in both doses (35 and 70 mg/kg) improved learning and memory processes in «T-maze test» test (p < 0.05). In addition, administration of metformin in small doses (35 and 70 mg/kg) It contributed to the development of the anxiolytic effect in «Elevated plus-maze» test and «Extrapolation escape task» tests (p < 0.05). It was shown that the administration of metformin (70 mg/kg) improved muscle endurance in «Rotarod» test (p < 0.05) against the background of unchanged glucose levels.

Conclusion. The results of the conducted studies determine the direction of further research on the possibility of using metformin in small doses that do not have a hypoglycemic effect for the correction of anxiety and cognitive disorders in pathological conditions of the CNS, including in the process of physiological aging.

About the Authors

A. Z. Hafizova
Kazan State Medical University of the Ministry of Health of Russia
Russian Federation

49, Butlerova str., Kazan, Republic of Tatarstan, Volga Federal District, 420012



D. O. Nikitin
Kazan State Medical University of the Ministry of Health of Russia
Russian Federation

49, Butlerova str., Kazan, Republic of Tatarstan, Volga Federal District, 420012



R. G. Sadykova
Kazan State Medical University of the Ministry of Health of Russia
Russian Federation

49, Butlerova str., Kazan, Republic of Tatarstan, Volga Federal District, 420012



V. B. Gavrilova
Kazan State Medical University of the Ministry of Health of Russia
Russian Federation

49, Butlerova str., Kazan, Republic of Tatarstan, Volga Federal District, 420012



A. V. Nikitina
Kazan State Medical University of the Ministry of Health of Russia
Russian Federation

49, Butlerova str., Kazan, Republic of Tatarstan, Volga Federal District, 420012



R. I. Moustafine
Kazan State Medical University of the Ministry of Health of Russia
Russian Federation

49, Butlerova str., Kazan, Republic of Tatarstan, Volga Federal District, 420012



I. I. Semina
Kazan State Medical University of the Ministry of Health of Russia
Russian Federation

49, Butlerova str., Kazan, Republic of Tatarstan, Volga Federal District, 420012



References

1. Hafizova A. Z., Semina I. I., Nikitin D. O., Mustafin R. I. Perspectives for the use of the antidiabetic drug metformin as a strategy to slow biological aging and age-related diseases. Kazan Medical Journal. 2025;106(1):105–116. (In Russ.) DOI: 10.17816/KMJ382686.

2. Hafizova A. Z., Semina I. I., Study of the possibility of using metformin by intranasal administration for the correction of behavioral and cognitive dysfunctions of rats. Pharmacokinetics and Pharmacodynamics. 2025;(1):35–42. (In Russ.) DOI: 10.37489/2587-7836-2025-1-35-42.

3. Markowicz–Piasecka M., Sikora J., Szydłowska A., Skupień A., Mikiciuk-Olasik E., Huttunen K. M. Metformin – a Future Therapy for Neurodegenerative Diseases. Pharmaceutical Research. 2017;34(12):2614–2627. DOI: 10.1007/s11095-017-2199-y.

4. Li Z., Zhang Z., Ren Y., Wang Y., Fang J., Yue H., Ma S., Guan F. Aging and age-related diseases: from mechanisms to therapeutic strategies. Biogerontology. 2021;22(2):165–187. DOI: 10.1007/s10522-021-09910-5.

5. Moskalev A., Guvatova Z., De Almeida Lopes I., Beckett C. W., Kennedy B. K., De Magalhaes J. P., Makarov A. A. Targeting aging mechanisms: pharmacological perspectives. Trends in Endocrinology & Metabolism. 2022;33(4):266–280. DOI: 10.1016/j.tem.2022.01.007.

6. LaMoia T. E., Shulman G. I. Cellular and Molecular Mechanisms of Metformin Action. Endocrine Reviews. 2021;42(1):77–96. DOI: 10.1210/endrev/bnaa023.

7. Triggle C. R., Mohammed I., Bshesh K., Marei I., Ye K., Ding H., MacDonald R., Hollenberg M. D., Hill M. A. Metformin: Is it a drug for all reasons and diseases? Metabolism. 2022;133:155223. DOI: 10.1016/j.metabol.2022.155223.

8. Li N., Zhou T., Fei E. Actions of Metformin in the Brain: A New Perspective of Metformin Treatments in Related Neurological Disorders. International Journal of Molecular Sciences. 2022;23(15):8281. DOI: 10.3390/ijms23158281.

9. Mohammed I., Hollenberg M. D., Ding H., Triggle C. R. A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan. Frontiers in Endocrinology. 2021;12:718942. DOI: 10.3389/fendo.2021.718942.

10. Guo J., Huang X., Dou L., Yan M., Shen T., Tang W., Li J. Aging and aging-related diseases: from molecular mechanisms to interventions and treatments. Signal Transduction and Targeted Therapy. 2022;7(1):391. DOI: 10.1038/s41392-022-01251-0.

11. Foretz M., Guigas B., Viollet B. Metformin: update on mechanisms of action and repurposing potential. Nature Reviews Endocrinology. 2023;19(8):460–476. DOI: 10.1038/s41574-023-00833-4.

12. Fan J., Li D., Chen H.-S., Huang J.-G., Xu J.-F., Zhu W.-W., Chen J.-G., Wang F. Metformin produces anxiolytic-like effects in rats by facilitating GABA A receptor trafficking to membrane. British Journal of Pharmacology. 2019;176(2):297–316. DOI: 10.1111/bph.14519.

13. Kang M., Liu H., Hui J., Gou Y., Zhou R., Liu Y., Liu C., Shi P., Wang B., Wen Y., Cheng B., Jia Y., Li C., Zhang F. Metformin use on the risks of depression and anxiety in people with type 2 diabetes. Communications Medicine. 2025;5(1):302. DOI: 10.1038/s43856-025-01006-2.

14. Morsli S., Bellantuono I. The use of geroprotectors to prevent multimorbidity: Opportunities and challenges. Mechanisms of Ageing and Development. 2021;193:111391. DOI: 10.1016/j.mad.2020.111391.

15. Aghaalikhani N., Goodarzi M. T., Latifi Z., Farimani A. R., Fattahi A. Effects of Different Doses of Metformin on Serum Fatty Acid Composition in Type 2 Diabetic Rats. Avicenna Journal of Medical Biochemistry. 2017;5(1):22–28. DOI: 10.15171/ajmb.2017.04.

16. Tahmi M., Benitez R., Luchsinger J. A. Metformin as a Potential Prevention Strategy for Alzheimer’s Disease and Alzheimer’s Disease Related Dementias. Journal of Alzheimer's Disease. 2024;101(s1):S345–S356. DOI: 10.3233/JAD-240495.

17. Allard J. S., Perez E. J., Fukui K., Carpenter P., Ingram D. K., de Cabo R. Prolonged metformin treatment leads to reduced transcription of Nrf2 and neurotrophic factors without cognitive impairment in older C57BL/6J mice. Behavioral Brain Research. 2016;301:1–9. DOI: 10.1016/j.bbr.2015.12.01.

18. Wu C. Y. C., Lerner F. M., Couto e Silva A., Possoit H. E., Hsieh T.-H., Neumann J. T., Minagar A., Lin H. W., Lee R. H. C. Utilizing the Modified T-Maze to Assess Functional Memory Outcomes After Cardiac Arrest. Journal of Visualized Experiments. 2018;(131):56694. DOI: 10.3791/56694.

19. Semina I. I., Baichurina A. Z., Nikitin D. O., Nikitina A. V., Moustafine R. I., Khutoryanskiy V. V. Behavioral Pharmacology as the Main Approach to Study the Efficiency of Potential Psychotropic Drugs: Analysis of Modern Methods (Review). Drug development & registration. 2023;12(1):161–181. (In Russ.). DOI: 10.33380/2305-2066-2023-12-1-161-181.

20. Titovich I. A., Radko S. V., Lisitskiy D. S., Okovitiy S. V., Bolotova V. Ts., Belskaya A. V., Mikhailova M. V., Sysoev Yu. I. The study of the effect of the aminoethanol derivative on cognitive functions of laboratory animals. Journal of Biomedicine. 2017;3:102–110. (In Russ.).

21. Shustov E. B., Okovityi S. V., Bolotova V. T., Kim T. E. Battery of tests for studying the adaptogenic effects of biologically active substances in preclinical trials. Pharmacy Formulas. 2021;3(2):10–25. (In Russ.). DOI:10.17816/phf65230.

22. Forouzandeh F., Salazar G., Patrushev N., Xiong S., Hilenski L., Fei B., Alexander R. W. Metformin Beyond Diabetes: Pleiotropic Benefits of Metformin in Attenuation of Atherosclerosis. Journal of the American Heart Association. 2014;3(6):e001202. DOI: 10.1161/JAHA.114.001202.


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Hafizova A.Z., Nikitin D.O., Sadykova R.G., Gavrilova V.B., Nikitina A.V., Moustafine R.I., Semina I.I. Study of the effect of metformin in small doses on the behavioral characteristics and biochemical parameters of rats. Drug development & registration. 2026;15(2):137-145. (In Russ.) https://doi.org/10.33380/2305-2066-2026-15-2-2186

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ISSN 2305-2066 (Print)
ISSN 2658-5049 (Online)