Long-term administration of metformin ameliorates age-dependent oxidative stress and cognitive function in rats

Aging is an inevitable physiological process, associated with a decline in cognitive function. Recently, metformin, as the first-line treatment for type II diabetes, has been shown to increase the life expectancy of diabetic patients. Therefore, researchers are paying increasing attention to its anti-aging properties. Oxygen free radicals are responsible for oxidative stress, which is a prominent factor in age-associated diseases. This study aimed to evaluate the effects of long-term administration of metformin on age-dependent oxidative stress and cognitive function.

In this experimental study, 32 normal (nondiabetic) male Wistar rats were randomly assigned into control and metformin groups (n = 16 per group). The metformin group received 100 mg/kg of metformin in drinking water daily for six months. The shuttle box test was used for the passive avoidance task in 24-month-old rats. For the biochemical assay, the total antioxidant capacity (TAC) and malondialdehyde (MDA) level were measured. Nissl and TUNEL staining were also used for histopathological assessments. Data were analyzed using independent t-test.

The present findings revealed that metformin significantly reduced the MDA level and increased the TAC in the hippocampus of the metformin group (p < 0.05). The survival of hippocampal CA1 neurons was significantly higher in the metformin group as compared to the control group, while the number of TUNEL-positive neurons decreased significantly (p < 0.05). On the other hand, metformin markedly improved the passive avoidance memory in the metformin group as compared to the control group (p < 0.05).

It can be concluded that long-term metformin intake, by modulating the oxidant/antioxidant mechanisms, prevents the loss of hippocampal neurons caused by age-dependent oxidative stress and improves memory.