Sex Dependent Alteration in Psychomotor and Cognitive Functions After Chronic Metformin Treatment

Purpose: Metformin, the most commonly used anti-hyperglycemic medication has been proposed to have delayed aging and longevity benefits. Without due consideration to gender/sex influence, metformin administration is being tested for non-diabetic benefits. Amid mixed reports on cognition, the purpose of the current study was to identify the influence of sex variation in the psychomotor and cognitive outcomes after long term metformin treatment. Materials and Methods: Young normo-glycemic male and female C57BL/6J mice (aged 4 mo, n=10 each; total n=40 mice) were randomly assigned to either a control group or metformin group (administered 2 mg/ml in drinking water). After 1 month of treatment, a battery of behavioral tests was initiated to assess the psychomotor and cognitive functions. Metformin treatment was continued during behavior assessment. Results: Overall female mice weighed lesser than male mice. Over the experiment time span, metformin neither altered the body weight nor decreased the blood glucose level significantly. There was no variation in muscle strength or reflexes between male and female mice on either treatment. Male mice were more anxious than female mice and metformin treatment decreased anxiety in male mice only. Female mice had better motor learning and maximum coordinated running performance than male mice. Metformin treatment improved motor learning only in male mice. Metformin treatment improved balance function irrespective of sex. Overall male mice had better retention of long term memory which was deteriorated after metformin treatment. Further, metformin impaired the short term memory and cognitive flexibility only in male mice. Conclusions: This study demonstrated that metformin affects psychomotor or cognitive function differently influenced by sex. Our results suggested that chronic metformin was beneficial for psychomotor function and detrimental for short term and long-term memory in male sex. While, in female sex, metformin had beneficial or no effects on brain functions.