Yokukansankachimpihange Improves the Social Isolation-Induced Sleep Disruption and Allopregnanolone Reduction in Mice.

Kenta Murata,Ryuji Takahashi,Misaki Ogata,Kanako Shinguchi,Feng Li,Nina Fujita

doi:10.3389/fnut.2020.00008

Abstract

Yokukansankachimpihange (YKSCH), a traditional Japanese medicine composed of 9 crude drugs, is designed to improve neurosis, insomnia in adults, and night crying in children. YKSCH has been reported to improve diurnal rhythm in patients with Alzheimer's disease and prolong the total sleeping time in healthy subjects. However, little is known about how YKSCH alleviates sleep disorders. Here, we investigated whether and how YKSCH treatment affected sleep latency and duration in group-housed and socially isolated mice. Male ddy mice were treated with YKSCH [1,500 mg/kg, per os (p.o.)] in group-housed or socially isolated conditions for 3–4 weeks. After the last injection, mice were intraperitoneally (i.p.) administered with pentobarbital (60 mg/kg) and the sleep latency and duration was evaluated. The results show that pretreatment with YKSCH had no effect on sleep latency or duration in group-housed mice. However, YKSCH treatment significantly improved the reduced sleep duration in socially isolated mice. This effect of YKSCH was inhibited by the administration of bicuculline (3 mg/kg, i.p.), a GABAA receptor antagonist. Furthermore, we showed that YKSCH treatment improved the decrease in allopregnanolone content and its synthase expression levels in the olfactory bulb. These results suggest that YKSCH treatment improved social isolation stress-induced insomnia via the GABAergic pathway and that the mechanism of action of YKSCH is partly due to improvement of allopregnanolone levels of expression.

Highlights

Yokukansankachimpihange (YKSCH), a traditional Japanese medicine, is designed to improve neurosis, insomnia in adults, and night crying in children
Both the latency and duration of sleep were not affected by YKSCH treatment [sleep latency; F [2, 15] = 0.913, p = 0.422, sleep duration; F(2, 15) = 4.959, p = 0.022]
In a previous clinical trial, Aizawa et al demonstrated that YKSCH treatment in healthy subjects extended the total sleeping time significantly, had no influence on rapid eye movement (REM) sleep, tended to increase stage 2 sleep, and decreased stage 3+4 sleep compared with Anchu-san as the control drug [3]

Summary

Introduction

Yokukansankachimpihange (YKSCH), a traditional Japanese medicine, is designed to improve neurosis, insomnia in adults, and night crying in children. YKSCH is composed of 9 herbs: Pinellia tuber, Atractylodes rhizome, Poria sclerotium, Cnidium rhizome, Citrus unshiu peel, Japanese Angelica root, Bupleurum root, Uncaria hook, and Glycyrrhiza. In addition to traditional use, YKSCH has been approved for administration to patients with dementia in Japan to treat behavioral and psychological symptoms of dementia (BPSD). A recent clinical trial revealed that YKSCH treatment improves the Neuropsychiatric Inventory scores of “agitation,” “delusion,” and “sleep and night-time behavior change” in patients with Alzheimer’s disease [1]. Other research revealed that a combination treatment of YKSCH with donepezil improved diurnal rhythm in patients with Alzheimer’s disease [2]. YKSCH treatment prolongs the total sleeping time and tends to increase sleep efficacy based on polysomnography recordings in normal young healthy subjects

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