Effect of yokukansan on memory disturbance in an animal model of cerebrovascular dementia

Yokukansan (YKS) is a traditional Japanese herbal medicine, which was reported to improve the behavioral and psychological symptoms of dementia (BPSD). However, the effect of YKS on memory dysfunction remains unknown. In this study, we examined the effect of YKS on impaired spatial memory in rats subjected to repeated cerebral ischemia, a well-established animal model for cerebrovascular dementia. Additionally, we compared the effect of YKS and donepezil (DPZ) on cholinergic dysfunction and hippocampal CA1 neuronal death in rats subjected to repeated cerebral ischemia. Spatial memory, as assessed using the eight-arm radial maze task, was impaired by repeated cerebral ischemia and significantly improved following administration of YKS (100, 300, 1000 mg/kg per day, p.o. for 14 days before and after ischemia treatment. Furthermore, a significant improvement was observed following additional 7-day treatment with YKS (1000 mg/kg per day, p.o.) after ischemia. YKS treatment was comparable to DPZ (10 mg/kg per day, p.o.) after ischemia. Microdialysis studies showed that spontaneous release of acetylcholine (ACh) from the dorsal hippocampus was significantly reduced following repeated cerebral ischemia. However, treatment with YKS or DPZ increased spontaneous ACh release following repeated cerebral ischemia. In contrast, hippocampal apoptosis, which developed after repeated ischemia, was suppressed by YKS, but not by DPZ. Overall, we found that YKS improves spatial memory disturbance via its unique character of having both an increasing effect on ACh release and a neuroprotective effect, which will be useful not only for BPSD but also memory dysfunction in cerebrovascular dementia patients.