Effects of α-lipoic acid on chronic cerebrovascular hypoperfusion in an animal model of vascular dementia

摘要

OBJECTIVE: Given the aging population, the treatment of vascular dementia (VaD) is becoming increasingly important. The antioxidant α-lipoic acid (α-LA) protects against neurodegeneration in VaD, but the underlying mechanisms remain unclear. Hence, we aimed to identify the effects of α-LA on cognitive function following chronic cerebrovascular hypoperfusion in a VaD animal model. MATERIALS AND METHODS: Mice were categorized into the sham, bilateral common carotid artery stenosis (BCAS), or BCAS + α-LA group. The BCAS + α-LA group was intraperitoneally injected (100 mg/kg) once daily with α-LA for 4 weeks after BCAS surgery, while the BCAS and sham groups were injected with saline. After the last injection, we examined cognitive function and exploration behavior using the Morris water maze. Mice brains were then harvested for Western blot analyses. RESULTS: The BCAS group, but not the BCAS + α-LA group, showed cognitive dysfunction in the Morris water maze. Apoptosis pathways involving poly (ADP-ribose) polymerase (PARP) cleavage, phosphorylated-mammalian target of rapamycin (p-mTOR), phosphorylated-3-phosphoinositide-dependent protein kinase-1, and phosphorylated-protein kinase B (p-AKT) were enhanced in the BCAS group than the α-LA group. The BCAS + α-LA group demonstrated less PARP cleavage and p-mTOR function than did the BCAS group. The activity of autophagy pathways involving LC3B was higher in the BCAS and BCAS + α-LA groups than the sham group, but there were no significant differences between the BCAS and BCAS + α-LA groups. CONCLUSIONS: In the BCAS rodent model, cognitive dysfunction and apoptosis mediated by the phosphatase and tensin homolog/AKT/mTOR pathway were observed in the hippocampus. However, acting on the mTOR pathway, α-LA improved cognitive function and led to hippocampal cell survival. Thus, α-LA may be useful for treating VaD.