The effect of metformin on behavioral characteristics and Bdnf gene expression of old rats with sex differences

Introduction: Ageing is a key risk factor for neurodegenerative diseases, so aging heightens the urgency of developing safe geroprotectors. Metformin is a compound of significant interest owing to its ability to modulate the pathogenesis of aging and related cognitive decline. Thus, the aim of the workwas to study the effects of metformin on behavior and Bdnf gene expression in the brains of aged rats with consideration of sex differences. Materials and Methods: The study was performed on 48 old (24 months) Wistar rats divided into groups (n=8): males and females receiving metformin (35 or 70 mg/kg/day) or saline (control) for 30 days. Anxiety (Elevated Plus maze test) and spatial memory (Water maze test) were assessed. The relative level of Bdnf gene expression was determined by real-time PCR. Results: Metformin at a dose of 70 mg/kg exerts an anxiolytic effect in males in the Elevated Plus maze test, increasing the duration of stay in the open ”arms” of the maze by 3.5 times (p=0.0443) and reducing the time of closed ”arms” by 1.5 times (p=0.0161) compared to those in the control group. Males also showed an improvement in spatial memory after the introduction of metformin at doses of 35 and 70 mg/kg in the Water Maze test: the duration of swimming in the platform zone increased by 1.7 times (35 mg/kg, p=0.04) and 1.5 times (70 mg/kg, p=0.03), respectively, compared to such in the control group. At a dose of 35 mg/kg, metformin causes a 3-fold increase in Bdnf gene expression in males in the prefrontal cortex (p=0.047) compared to such in the control group. In females, Bdnf gene expression in the cerebellum positively correlates with spatial memory (p=0.039), which emphasizes its role in cognitive functions. Conclusion: A 30-day metformin treatment exerted pronounced anxiolytic (70 mg/kg) and mnemotropic effects (35 and 70 mg/kg) in aged male rats, correlating with elevated prefrontal cortex Bdnf geneexpression. In females, spatial memory improvement correlated with cerebellar Bdnf gene upregulation.