Identification of oxytocin receptor activating chemical components from traditional Japanese medicines

Abstract

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 Ca 2+ ([Ca 2+ ] 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 [Ca 2+ ] 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 ( Zizyphi 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.

Traditional Japanese medicine Kamikihito ameliorates sucrose preference, chronic inflammation and obesity induced by a high fat diet in middle-aged mice

“…How KKT suppresses inflammation in liver and adipose tissue remains unclear. However, considering our previous report, which demonstrated the capability of KKT to activate OXTR ( 30 ), at least two mechanisms can be considered for its anti-inflammation mechanism; first, KKT directly affects hepatocytes and adipocytes; second, KKT affects macrophages within the liver and adipose tissues.…”

“…The KKT (500 mg/kg/5ml) was dissolved in distilled water for oral administration. The dose of KKT was based on the prior studies of KKT (200–2000 mg/kg oral administration in mice or rats) ( 30 , 35 , 36 ). KKT (Lot No.…”

“…KKT has been reported to attenuate depressive-like behavior ( 28 ), and increase oxytocin secretion in cerebrospinal fluid in rats with acute stress ( 29 ). Our previous study clearly demonstrated that KKT activates oxytocin receptors (OXTR) and functions as an agonist ( 30 ). It is considered that KKT promotes oxytocin secretion by activating OXTR expressed in oxytocin neurons ( 30 ), and may alleviate neuropsychological stress disorders.…”

“…Our previous study clearly demonstrated that KKT activates oxytocin receptors (OXTR) and functions as an agonist ( 30 ). It is considered that KKT promotes oxytocin secretion by activating OXTR expressed in oxytocin neurons ( 30 ), and may alleviate neuropsychological stress disorders.…”

Expression of oxytocin in hypothalamus and reduction of nociceptive stress following administration of Kamikihi-to in female rats

“…KKT has been approved by the Ministry of Health, Labour and Welfare in Japan since 1986, with indications for anemia, insomnia, anxiety, and neurosis. Maejima et al (2021) reported that report a relationship between KKT treatment and OXT neuron activity by electrophysiological experiments. OXT neuron in the PVN of the hypothalamus are stimulated by KKT administration, which exerts an anti-stress response and increases OXT secretion in the cerebrospinal fluid ( Tsukada et al, 2021 ).…”