Aerobic exercise and metformin 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 geriatric population. Aerobic exercise is an excellent non-pharmacological therapeutic strategy to prevent Alzheimer's disease, the most common form of dementia. The exact molecular mechanism of aerobic exercise (Exe) as an intervention to counter cognitive decline is far from clear. Metformin is a first-line agent against T2DM with neuroprotective properties. The present study assessed the role of treadmill exercise in combination with a low dose of metformin (Met; 70 mg/kg) in cognitive impairment and its associated molecular mechanism in T2DM rats. The experimental model of T2DM-associated cognitive decline was created by administration of a high-fat diet (HFD) with a low dose of streptozotocin (STZ; 35 mg/kg). Neurobehavioral assessments were performed to evaluate spatial recognition and fear-conditioned memory across the groups: control, HFD + STZ, HFD + STZ + Exe, and HFD + STZ + Exe + Met. In addition, we performed immunohistochemistry and western blotting on the rat hippocampal tissue from the above groups for protein expression studies. T2DM rats showed a significant cognitive decline compared to the control group, which improved in the long-term 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. T2DM reduced mature neurons and neurogenesis while increasing astrogliosis and microgliosis, ameliorated by exercise and metformin treatment. Moreover, T2DM impaired hippocampal neurogenesis by reducing the canonical Wnt/β-catenin pathway, which got upregulated in exercise and metformin-co-administered rats. 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.