Vitamin D(3) alleviates cognitive impairment through regulating inflammatory stress in db/db mice

Patients with type 2 diabetes mellitus (T2DM) have a higher risk to develop cognitive impairment. Several studies reported the potential roles of vitamin D in prevention of cognitive impairment, but the mechanism remains unclear. The present study aims to investigate the protective effects of vitamin D(3) on cognitive impairment in db/db mice and to explore the possible mechanism. Twelve‐week‐old male db/db mice were randomly administrated with low, medium, and high dose of vitamin D(3) (LVD, MVD, and HVD groups, respectively) and equivalent volume vitamin D(3) solvent (corn oil, DM group) intragastrically. Eight age‐matched db/m mice were given equivalent volume corn oil as normal group. After 16 weeks of vitamin D(3) treatment, the concentrations of fasting serum glucose in three vitamin D(3) groups (especially the 1,000 IU/kg·bw dose) were significantly decreased compared with DM group. Pathology revealed that the neuron damage was reduced in vitamin D(3) groups. MVD intervention significantly shortened the escape latency on day 5 and extended time in the target quadrant. Mice in HVD group had significantly higher exploration time and discrimination index compared with the DM group mice. Moreover, vitamin D(3) treatment has increased the phosphorylation of cAMP‐response element‐binding protein and the expression of brain‐derived neurotrophic factor and vitamin D receptor. This treatment, meanwhile, has decreased the expression of tumor necrosis factor‐α, the phosphorylation of inhibitor kappa Bα (IκBα), and nuclear factor‐κB p65 (NF‐κB p65) in the hippocampus of db/db mice. These results suggest that vitamin D(3) alleviated cognitive impairment in the hippocampus of db/db mice. Down‐regulation of the NF‐κB signaling pathway‐related proteins IκBα and p65 might be one of the possible mechanisms.