Yokukansan, a Traditional Japanese Medicine, Suppresses Stress-Induced Sympathetic Activation via Central Responses in Rats

Abstract

Objectives: Yokukansan (YKS) is a traditional Japanese Kampo medicine approved by the Ministry of Health, Labour and Welfare of Japan. Recently, in addition to its indications as a drug treatment, YKS has been shown to have ameliorative effects on various psychological and behavioral responses such as anxiety, aggression, and stress responses. Stress exposure activates not only the hypothalamic–pituitary–adrenal axis but also the sympathetic nervous system. Sympathetic activation in brain regions such as the paraventricular hypothalamic nucleus (PVN) stimulates elevation of plasma catecholamine (noradrenaline and adrenaline) levels. We previously reported that various stress-related neuropeptides and several kinds of stressors, such as restraint stress (RS), increase plasma catecholamine and that brain prostanoids and their synthases mediate these responses in rats. In the present study, to determine if YKS treatment can affect stress-induced sympathetic activation, we examined the effects of YKS treatment on the RS-induced elevation of plasma catecholamine levels and related prostanoid production in the PVN of rats. Methods: YKS (1000 mg/10 mL/kg, p.o.) or vehicle was administered to rats daily for 14 days, and all rats were exposed to RS for 60 min on day 14. Before and during stress exposure on day 14, blood samples and PVN dialysates were collected and analyzed by high-performance liquid chromatography and liquid chromatography-ion trap tandem mass spectrometry, respectively. Results: Our results showed that repeated administration of YKS suppressed the RS-induced increase in plasma adrenaline but not noradrenaline. Furthermore, YKS administration also suppressed the RS-induced elevation of both prostaglandin E2 and thromboxane B2 levels in the PVN. In addition, we found that repeated administration of YKS suppressed the RS-induced increase in serotonin, gamma-aminobutyric acid, and acetylcholine in the PVN. Conclusion: Our results suggest that YKS can ameliorate stress-induced sympathetic activation via inhibition of stress responses in the brain.