Identification of oxytocin receptor activating chemical components from traditional Japanese medicine

Yuko Maejima ^a,**, Shoichiro Horita ^a, Shoko Yokota ^a, Tomoyuki Ono ^a, Peter Proks ^b, Hiromi Yoshida-Komiya ^c, Yoichi Ueta ^d, Katsuhiko Nishimori ^a, Shingen Misaka ^a, Kenju Shimomura ^a,*

a Department of Bioregulation and Pharmacological Medicine, Fukushima Medical University School of Medicine, Fukushima, 960-1295, Japan

b Oxford Centre for Gene Function, University of Oxford, Oxford, OX1 3PT, United Kingdom

c Gender Specific Medical Centre, Fukushima Medical University School of Medicine, Fukushima, 960-1295, Japan

d Department of Physiology, School of Medicine, University of Occupational and Environmental Health, Kita-Kyushu, 807-8555, Japan

Oxytocin (Oxt) is known to regulate social communication, stress and body weight. The activation of Oxt receptors (OTR) has clinical potential to abate stress disorders and metabolic syndrome. Kamikihito (KKT) is a traditional Japanese medicine used to treat psychological stress-related disorders. We investigated the effects of KKT, its ingredients and chemical components on Oxt neurons and OTR. C-Fos expression was examined after oral and peripheral administration of KKT in rats. Electrophysiological change of Oxt neurons and Oxt release upon application of KKT were measured in rat brain slice. The direct effect of KKT, its ingredients and its chemical components were examined by cytosolic Ca2+ ([Ca2+]i) measurement in Oxt neurons and OTR-expressing HEK293 cells. Both intraperitoneal and oral administration of KKT in rats induced c-Fos expression in neurons of the paraventricular nucleus (PVN) including Oxt neurons. Application of KKT induced activation of Oxt neurons and Oxt release. KKT increased [Ca2+]i in OTR-expressing HEK293 cells, and failed to activate with OTR antagonist. KKT-induced PVN Oxt neuron activation was also attenuated by OTR antagonist. Seven chemical components (rutin, ursolic acid, (Z)-butylidenephtalide, p-cymene, senkunolide, [6]-shogaol, [8]-shogaol) of three ingredients (Zyzyphi Fructus, Angelicae Acutilobae Radix, Zingiberis Rhizoma) from KKT had potential to activate OTR. KKT can directly activate PVN Oxt neurons by interacting with OTR. The interaction of seven chemical components from KKT may contribute to activate OTR. Effect of KKT on Oxt neurons and OTR may contribute to the treatment of Oxt related disorders.

Keywords: Kamikihito, Oxytocin neuron, Oxytocin receptor, Traditional Japanese medicine

https://doi.org/10.38212/2224-6614.3381