Abstract
Many medicinal plants have been used in Asia for treating a variety of mental diseases, including insomnia and depression. However, their sedative–hypnotic effects and mechanisms have not been clarified yet. Accordingly, the objective of this study was to investigate the sedative–hypnotic effects of water extracts of five medicinal plants: Coptidis Rhizoma, Lycii Fructus, Angelicae sinensis Radix, Bupleuri Radix, and Polygonum multiflorum Thunberg. The binding abilities of five medicinal plant extracts to the GABAA–BZD and 5-HT2C receptors were compared. Their abilities to activate arylalkylamine N-acetyltransferase (AANAT), a melatonin synthesis enzyme, in pineal cells were also determined. Following in vitro tests, the sedative and hypnotic activities of extracts with the highest activities were determined in an animal sleep model. In the binding assay, the water extracts of Coptidis Rhizoma (WCR) showed high binding affinity to the GABAA–BZD and 5-HT2C receptors in a dose-dependent manner. Additionally, WCR increased the AANAT activity up to five times compared with the baseline level. Further animal sleep model experiments showed that WCR potentiated pentobarbital-induced sleep by prolonging the sleep time. It also decreased the sleep onset time in mice. In addition, WCR reduced wake time and increased non-rapid eye movement (NREM) sleep without EEG power density (percentages of δ, θ, and α waves) during NREM sleep in rats. WCR could effectively induce NREM sleep without altering the architectural physiologic profile of sleep. This is the first report of the sedative–hypnotic effect of Coptidis Rhizoma possibly by regulating GABAA and 5-HT2C receptors and by activating AANAT activity.
Highlights
It enhanced pentobarbital-induced sleep in the animal model. These results suggest that the hypnotic activity of water extracts of Coptidis Rhizoma (WCR) might be due to the binding of 5-HT2C and GABAA receptors and arylalkylamine N-acetyltransferase (AANAT) activity
Because AANAT is known to control the night/day rhythm of melatonin production in the pineal gland, which plays critical roles in the circadian regulation of sleep–wake cycles, as it attenuates wake-promoting signals of the suprachiasmatic nucleus (SCN) while promoting the consolidation of sleep, we investigated the effects of WCR on AANAT
Melatonin is known to increase the concentration of GABA in the hypothalamus [39], potentiate GABA turnover, and cause an enhancement of GABA binding [40]. These results suggest that WCR produces its hypnotic and anxiolyticlike effects through interaction with the GABAA and 5-HT2c receptors, both of which are known to play a critical role in sleep functions
Summary
Sleep disorder or sleep loss can cause the dysregulation of homeostasis and lead to the impairment of immune functioning, which could be a significant factor contributing to a variety of inflammatory and chronic diseases. 15% of the adult population suffers from long-term insomnia, and these values are still higher among adults with concomitant medical or psychiatric disorders [1]. Therapy for sleep disorders includes sedative–hypnotic medications, such as benzodiazepines (BZD)/non-BZD (GABAA receptor agonists), sedating antidepressants (tricyclic antidepressant, 5-hydroxytryptamine receptor antagonists), and antihistamines [2]. Drugs, including hypnotic medications generally used for treating sleep disorders, are associated with side effects, such as mood disorders, lung diseases, and cognitive deficits [3–8]. Interest in herbal drugs as alternatives to prescribed medicine is increasing to enhance the quality of sleep and avoid adverse outcomes
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