Fighting Against Aging-Related Dysfunction Under Variable Stress: Possible Antioxidant and Neuroprotective Roles of Metformin via Increased Superoxide Dismutase and Brain-Derived Neurotrophic Factor

Background: Chronic stress causes a deleterious impact on older adults and accelerates the aging process through different mechanisms, such as increased oxidative stress. Metformin, a drug with pleiotropic effects, exhibited neuroprotective and antioxidant properties. Objectives: Our study aimed to investigate the metformin effects on aging under stress conditions. Methods: Old male rats (18 months) were divided into 6 experimental groups (N = 8): 1 = control; 2 and 3 = metformin (1 or 10 mg/kg, orally, 40 days); 4 = stress (40 days); 5 and 6 = stress + metformin (1 or 10 mg/kg, orally, 40 days). Chronic variable stress was induced with 7 types of stressors for 40 days. Neurobehavioral functions were evaluated using the Morris water maze, Y-maze, elevated plus maze, open field, forced swimming test, rotarod, and exhausting swimming test. In addition, BDNF level and SOD activity were measured. Results: Stress induction increased memory deficits, anxiety, depression, and muscle fatigue in old rats. Metformin (10 mg/kg) enhanced memory performance and muscle strength and diminished anxiety and depression in stressed animals (P < 0.05). Treatment with metformin increased the BDNF brain level and SOD activity (P < 0.05). Conclusions: Metformin restored neurobehavioral disruptive changes induced by chronic stress in old rats. The underlying mechanisms could be related to the prevention of oxidative stress and neuronal damage and elevation of BDNF levels in the brain.