Yokukansan, a traditional Japanese herbal medicine, promotes neurite outgrowth in PC12 cells through the activation of extracellular signal regulated kinase 1/2 and phosphatidylinositol 3-kinase/Akt

Abstract

Neurotrophic factor-like substances and inducers of neurotrophic factor biosynthesis have the clinical potential for serious neuronal diseases such as Alzheimer's disease (AD). Yokukansan (YKS) is a traditional Japanese herbal medicine consisting of seven medicinal herbs which has been used to treat anxiety disorder, insomnia, and the behavioral and psychological symptoms of dementia (BPSD) in Japan. In this study, we report the first investigation of the neurotrophic activity and mechanism of YKS in PC12 pheochromocytoma cells as a model of neuronal differentiation. YKS promoted neurite extension and increased the numbers of neurites in a dose dependent manner (0.1-1.0 mg/ml) similar to nerve growth factor (NGF) treatment. Our finding showed that YKS treatment significantly activated extracellular signal regulated kinase 1/2 (ERK1/2) and phosphatidylinositol 3-kinase (PI3K)/Akt, and inhibition of these kinases with the respective pharmacological inhibitors effectively attenuated YKS-induced neurite outgrowth in PC12 cells. We also found that addition of K-252a, a TrkA antagonist, significantly inhibited NGF- but not YKS-induced neurite outgrowth. These results indicate that YKS induces neurite outgrowth, at least in part, through the activation of ERK1/2 and PI3K/Akt-dependent but TrkA-independent pathways. We suggest that this neurotrophic activity of YKS is also neuroprotective and cause the amelioration of BPSD. Thus, these findings indicate that YKS might be useful as a pharmacological tool for only BPSD but also the cognitive disorder and as novel leading compound for drug development for AD.