Study of the possibility of using metformin by intranasal administration for the correction of behavioral and cognitive dysfunctions of rats

Relevance. Metformin is an antidiabetic agent in the therapy of type 2 diabetes mellitus, which has a complex of pharmacological effects that may allow its use as a geroprotector and a means for the treatment of cognitive and behavioral disorders. Metformin when administered orally has low bioavailability (50–60 %), as well as the risk of side effects, which is the rationale for studying the intranasal route of administration of metformin.

Objective. To investigate the behavioral effects of metformin during intranasal administration as a rationale for the development of its intranasal dosage form.

Materials and methods. The object of the study was metformin administered intranasally (i/n) to rats at a dose of 70 mg/kg. The intragastric (i/g) route of administration (70 mg/kg) was used for comparison. After 30-day i/n and i/g administration of metformin, the rats were subjected to behavioral tests: the T-Maze test, Water Maze test, Elevated Plus-Maze test (EPM), and Extrapolation Escape task (EE). The Student's t-test in Graph pad Prism 8.0.1 program was used for statistical processing.

Results. When administered i/n, there was 5.6 times (p = 0.022) decrease in the latent period of arm selection (p = 0.022), and when administered i/g, there was 2.9 times (p = 0.01) decrease in the “T-maze”test compared to the control. No statistically significant result was found in the “EPM”test when applied i/n, in contrast to i/g, in which the duration of stay of rats in the OА of the maze was 3.0 times (p = 0.01) more than the control, and in the CA — 1.3 times (p = 0.01) less. In the “EE” test, i/n administration of metformin contributed to 5.1 times (p = 0.02) decrease in jump duration compared to control. In case of i/g administration metformin, the duration of the jumping period was 2.9 times shorter (p = 0.038).

Conclusion. Intranasal administration of metformin can be considered as an alternative way of its use and be the basis for the development of a system of directed delivery of metformin.

1. Markowicz-Piasecka M, Sikora J, Szydłowska A, et al. Metformin – a Future Therapy for Neurodegenerative Diseases : Theme: Drug Discovery, Development and Delivery in Alzheimer's Disease Guest Editor: Davide Brambilla. Pharm Res. 2017 Dec;34(12):2614-2627. doi: 10.1007/s11095-017-2199-y.

2. Li N, Zhou T, Fei E. Actions of Metformin in the Brain: A New Perspective of Metformin Treatments in Related Neurological Disorders. Int J Mol Sci. 2022 Jul 27;23(15):8281. doi: 10.3390/ijms23158281.

3. Alharbi I, Alharbi H, Almogbel Y, et al. Effect of Metformin on Doxorubicin-Induced Memory Dysfunction. Brain Sci. 2020 Mar 7;10(3):152. doi: 10.3390/brainsci10030152.

4. Ashrostaghi Z, Ganji F, Sepehri H. Effect of metformin on the spatial memory in aged rats. National Journal of Physiology, Pharmacy and Pharmacology. 2015;5(5):416-420. doi: 10.5455/njppp.2015.5.1208201564.

5. Zhang W, Zhao L, Zhang J, Li P, Lv Z. Metformin improves cognitive impairment in diabetic mice induced by a combination of streptozotocin and isoflurane anesthesia. Bioengineered. 2021 Dec;12(2):10982-10993. doi: 10.1080/21655979.2021.2004978.

6. Bułdak Ł, Łabuzek K, Bułdak RJ, et al. Metformin affects macrophages' phenotype and improves the activity of glutathione peroxidase, superoxide dismutase, catalase and decreases malondialdehyde concentration in a partially AMPK-independent manner in LPS-stimulated human monocytes/ macrophages. Pharmacol Rep. 2014 Jun;66(3):418-29. doi: 10.1016/j.pharep.2013.11.008.

7. Fan J, Li D, Chen HS, et al. Metformin produces anxiolytic-like effects in rats by facilitating GABAA receptor trafficking to membrane. Br J Pharmacol. 2019 Jan;176(2):297-316. doi: 10.1111/bph.14519.

8. Porfiryeva NN, Semina II, Moustafine RI, Khutoryanskiy VV. Intranasal Administration as a Route to Deliver Drugs to the Brain (Review). Drug development & registration. 2021;10(4):117-127. (In Russ.). doi: 10.33380/2305-2066-2021-10-4-117-127.

9. Mironov AN, Bunyatyan ND, Vasiliev AN, et al. Guidelines for conducting preclinical studies of drugs. Part One. Moscow: Grif i K, 2012. (In Russ.).

10. Semina II, Baichurina AZ, Nikitin DO, et al. 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.

11. Titivich IA, Radko SV, Lisitskiy DS, et al. The study of the effect of the aminoethanol derivative on cognitive functions of laboratory animals. Biomedicine. 2017;(3):102-110. (In Russ.).

12. Yakimova NL, Sosedova LM. Dophamine-dependent disorder of conduct of albino rats with sublimate intoxication in the test of extrapolation deliverance. Acta Biomedica Scientifica. 2013;1(89):130-133. (In Russ.).

13. Łabuzek K, Suchy D, Gabryel B, Bielecka A, Liber S, Okopień B. Quantification of metformin by the HPLC method in brain regions, cerebrospinal fluid and plasma of rats treated with lipopolysaccharide. Pharmacol Rep. 2010 Sep-Oct;62(5):956-65. doi: 10.1016/s1734-1140(10)70357-1.

14. Crowe TP, Greenlee MHW, Kanthasamy AG, Hsu WH. Mechanism of intranasal drug delivery directly to the brain. Life Sci. 2018 Feb 15;195:44-52. doi: 10.1016/j.lfs.2017.12.025.

15. Sharma G, Sharma AR, Lee SS, et al. Advances in nanocarriers enabled brain targeted drug delivery across blood brain barrier. Int J Pharm. 2019 Mar 25;559:360-372. doi: 10.1016/j.ijpharm.2019.01.056.

16. Kao HD, Traboulsi A, Itoh S, et al. Enhancement of the systemic and CNS specific delivery of L-dopa by the nasal administration of its water soluble prodrugs. Pharm Res. 2000 Aug;17(8):978-84. doi: 10.1023/a:1007583422634.

17. Hafizova AZ, Semina II, Nikitin DO, et al. 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.