Metformin alleviates the cognitive impairment induced by benzo[a]pyrene via glucolipid metabolism regulated by FTO/FoxO6 pathway in mice

Abstract

Benzo[a]pyrene (B[a]P) is neurotoxic; however, the mechanism and prevention are still unclear. In this study, we assessed the intervention effect of metformin (MET) on cognitive dysfunction in mice induced by B[a]P from the perspective of glucolipid metabolism. Forty-two male healthy ICR mice were randomly categorized into 6 groups and were gavaged with B[a]P (0, 2.5, 5, or 10 mg/kg), 45 times for 90 days. The controls were gavaged with edible peanut oil, and the intervention groups were co-treated with B[a]P (10 mg/kg) and MET (200 or 300 mg/kg). We assessed the cognitive function of mice, observed the pathomorphological and ultrastructural changes, and detected neuronal apoptosis and glucolipid metabolism. Results showed that B[a]P dose-dependently induced cognitive impairment, neuronal damage, glucolipid metabolism disorder in mice, and enhanced proteins of fat mass and obesity-associated protein (FTO) and forkhead box protein O6 (FoxO6) in the cerebral cortex and liver, which were alleviated by the MET intervention. The findings indicated the critical role of glucolipid metabolism disorder in the cognitive impairment in mice caused by B[a]P and the prevention of MET against B[a]P neurotoxicity by regulating glucolipid metabolism via restraining FTO/FoxO6 pathway. The finding provides a scientific basis for the neurotoxicity and prevention strategies of B[a]P.

Keywords: Benzo[a]pyrene; Cognitive impairment; Fat mass and obesity-associated protein; Forkhead box protein O6; Glucolipid metabolism; Metformin.