Aerobic exercise and metformin co-administration attenuate the cognitive impairment in an experimental model of type 2 diabetes mellitus: Focus on neuroinflammation and adult hippocampal neurogenesis

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder that increases the prevalence of cognitive impairment in the elderly. Aerobic exercise has been reported as an excellent non-pharmacological therapeutic strategy to prevent Alzheimer’s disease and dementia. The present study assessed the role of treadmill exercise and metformin (70 mg/kg) co-administration for fourteen weeks in cognitive impairment and its associated molecular mechanism in T2DM rats. Neurobehavioural assessments were performed to evaluate spatial recognition and fear-conditioned memory. ELISA was performed to evaluate the inflammatory cytokines in the hippocampus of diabetic rats. Furthermore, immunohistochemistry and western blotting confirmed the effect of exercise and metformin on astrogliosis and adult hippocampal neurogenesis. T2DM rats showed a significant alteration in neurobehavioural patterns compared to the control group, which were improved in the exercise and metformin co-administered animals. The level of neuroinflammation was significantly elevated in the hippocampal tissue of T2DM rats compared to the control and lowered after exercise and metformin treatment. Molecular expression of mature neurons, astrogliosis, microgliosis, and neurogenesis markers were significantly altered in T2DM rat brains and ameliorated upon exercise and metformin treatment. Moreover, upregulation of the canonical Wnt/β-catenin pathway in the hippocampus was observed in exercise and metformin co-administered rats, which was impaired in the T2DM hippocampus. In summary, long-term aerobic exercise with metformin treatment ameliorated neuroinflammation and promoted adult hippocampal neurogenesis via upregulating the canonical Wnt/β-catenin pathway in T2DM rats.