Effect of metformin treatment on memory and hippocampal neurogenesis decline correlated with oxidative stress induced by methotrexate in rats.

Metformin is currently used as a first-line drug to treat patients with type 2 diabetes. Previous studies have demonstrated that metformin has antioxidant properties and reduces neuroinflammation and hippocampal neuronal cell loss, which eventually improves memory. Methotrexate (MTX) is an antimetabolite chemotherapeutic agent reported to activate cognitive impairment found in many patients. Moreover, MTX negatively affects the spatial working memory, related to neurogenesis reduction in animal models. Therefore, the present study aimed to investigate the antioxidant effect of metformin on the reduction of memory and neurogenesis caused by MTX. Male Sprague-Dawley rats were divided into four groups: control, MTX, metformin, and MTX+metformin. MTX (75 mg/kg, i.v.) was administered on days 7 and 14. Rats were administered metformin (200 mg/kg, i.p.) for 14 days. Memory was determined using novel object location (NOL) and novel object recognition (NOR) tests. Furthermore, cell cycle arrest was quantified by p21 immunostaining. Levels of neuronal protein expression, scavenging enzymes activity, and malondialdehyde (MDA) level changes in the hippocampus and prefrontal cortex were investigated. Rats receiving only MTX showed memory impairment. Decreases in scavenging enzyme activity and BDNF, DCX, and Nrf2 protein expressions levels were detected in the MTX-treated rats. In addition, MTX significantly increased p21-positive cell numbers and MDA levels. However, these adverse MTX effects were counteracted by co-administration with metformin. These results demonstrate that metformin can improve memory impairments, increase BDNF, DCX and Nrf2 protein expressions and antioxidant capacities, and decrease MDA levels in MTX-treated rats.