Yokukansan Appears to Regulate Epidermal Glutamate Signaling, Notably NMDA Receptors, in the Epidermis

Abstract

Yokukansan (YKS) has been used in Japan as a remedy for neurosis, insomnia, and children with night crying. Recently, many studies on the central nervous system (CNS) in terms of the effect of YKS have been reported in Japan. Here, we introduce our studies of YKS effects in the dermatological field. Our first study showed that YKS controls scratching behaviors and inhibits the development of AD-like lesions in isolated NC/Nga mice. In the second study, we compared the efficacy of YKS and fexofenadine (anti-allergic drug) using the same experimental system. Both YKS and fexofenadine inhibit aggravation of AD-like symptoms in socially isolated NC/Nga mice with respect to TEWL and dermatitis scores. However, YKS decreases the scratching and grooming behaviors in socially isolated NC/Nga mice. Thus, we speculate that YKS inhibits the aggravation of AD-like skin lesions in isolated NC/Nga mice due to mechanisms different from fexofenadine. From the results for the central nervous system, we focused on glutamate signaling to evaluate the effect of YKS in the epidermis. Immunohistochemistry and RT-PCR revealed that N-methyl-D-aspartate (NMDA) receptor expression was increased in the skin of conventional control mice and was decreased in YKS-treated mice. Glutamate transporter-1 (GLT-1) mRNA levels were decreased in the skin of conventional control mice and were increased in YKS-treated mice. The results indicate that YKS ameliorates AD-like skin lesions in NC/Nga mice through a mechanism distinct from that of fexofenadine. Our latest experiment showed that the extracellular concentrations of glutamate increased as the cell density increased in cultured keratinocytes. We speculate that this increase originated from an outflow of glutamate from the keratinocytes. Furthermore, the effects of YKS are suggested to regulate epidermal glutamate signaling, notably NMDA receptors, in the epidermis.