Comparison of the Effects of Yokukansan and Yokukansankachimpihange on Glutamate Uptake by Cultured Astrocytes and Glutamate-Induced Excitotoxicity in Cultured PC12 Cells

The traditional Japanese Kampo medicine yokukansan (YKS) is effective for behavioral and psychological symptoms of dementia (BPSD) in patients with Alzheimer's disease. As the pharmacological mechanisms, YKS is known to protect astrocytes from thiamine-deficiency (TD)-induced decreased glutamate (Glu) uptake and neuron model cells (PC 12 cells) from Glu-induced death. Yokukansankachimpihange (YKSCH) is an alternative formula to YKS, in which Citrus unshiu peel and Pinellia tuber are added to the YKS components, and is sometimes used to treat BPSD, but its pharmacological properties remain unknown. This study aims to investigate the cellular pharmacological effects of YKS and YKSCH on glutamatergic pathways, compare their efficacy, and determine the differences and similarities in the activities between these formulations. First, we examined the effects of YKS and YKSCH on Glu uptake by cultured astrocytes under TD conditions. We observed significant ameliorative effects of YKS and YKSCH on the TD-induced decrease in Glu uptake, with a 50% effective dose of 8.9 ± 1.8 μg/mL and 45.3 ± 9.2 μg/mL, respectively. Second, using cultured PC12 cells as a model for neurons, we examined the effects of YKS and YKSCH on Glu-induced cell death. We observed that YKS and YKSCH had significant inhibitory effects on Glu-induced cell death, with a 30% effective dose of 51.4 ± 20.8 μg/mL and 49.2 ± 11.0 μg/mL, respectively. Thus, while YKSCH was less effective than YKS in ameliorating the TD-induced decrease in Glu uptake by astrocytes, the two drugs showed similar inhibitory effects on Glu-induced PC12 cell death. These findings are important for understanding the differences and similarities in pharmacological actions between these drugs.