Ursolic acid improves cognitive impairment in type 2 diabetic mice by preventing complement 3 secretion and neuropathy

BACKGROUND: Type 2 diabetes mellitus (T2DM) and cognitive impairment are high incidence epidemics worldwide and are recognized as comorbidities. Ursolic acid (UA) is considered as a potential therapy for diabetic cognitive impairment due to its neuroprotective effect. This study focused on the therapeutic efficacy and possible mechanisms of UA in restoring cognitive function in T2DM mice. METHODS: C57BL/6 male mice were fed with high-fat diet combined with intraperitoneal injection of streptozotocin to establish a T2DM model, and then were treated with UA or vehicle by oral administration for 21 days. The cognitive performance was determined using the T-maze test and novel object recognition test. The levels of complement C3, C3aR, GSK3β, neuronal damage, GFAP, Iba-1, pathological tau and proinflammatory cytokines such as IL-1β and TNF-α in prefrontal cortex of the T2DM mice were evaluated by western blot, tissue staining, or ELISA. The effect of UA on high glucose-induced cytotoxicity was assessed by MTT assay, and the effects of UA on proinflammatory cytokines and C3 were detected by ELISA and western blot. RESULTS: We showed that administration of UA prevented neuronal damage, neuroinflammation and tau hyperphosphorylation by suppressing C3-C3aR-GSK3β axis, resulting in a significant improvement of cognition in T2DM mice. UA inhibited C3 expression and lowered the production of proinflammatory cytokines to resist high glucose induced cytotoxicity in vitro. CONCLUSION: Our results suggest that UA supplements have cognitive protective effects on the T2DM mouse model and may be a promising candidate drug for cognitive impairment.