Rhus parviflora and its biflavonoid constituent, rhusflavone, induce sleep through the positive allosteric modulation of GABA_A-benzodiazepine receptors

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• 作者：Sabina Shrestha^a ; Ji-Hae Park^a ; Dae-Young Lee^a ; Jin-Gyeong Cho^a ; Suengmok Cho^b ; Hye-Jin Yang^b ; Hye-Im Yong^b ; Min-Seok Yoon^b ; Dae-Seok Han^b ; Nam-In Baek^a ; ^{nibaek@khu.ac.kr}
• 关键词：BBB ; blood-brain barrier ; BZD ; benzodiazepine ; c.c. ; column chromatography ; CHCl3 ; chloroform ; CMC ; carboxymethyl cellulose ; CNS ; Central nervous system ; CON ; control group ; DPM ; disintegrations per minute ; DW ; distilled water ; DZP ; diazepam ; EtOAc ; ethyl
• 刊名：Journal of Ethnopharmacology
• 出版年：2012
• 期刊代码：26_03788741
• 类别：pha
• 出版时间：26 June, 2012
• 卷：142
• 期：1
• 页码：213-220
• 文件大小：377 K

摘要

Ethnopharmacological relevance

Rhus parviflora is referred as 鈥楾intidikah鈥?in traditional medicinal system of south Asia (Ayurveda). It is used in treatment of V膩ta vik膩ra, a condition related to neurological complications as well as cure for stomach disorders.

Materials and methods

Dried and powdered fruits of R. parviflora were extracted with 80%aqueous methanol (RPME). The concentrated extract was successively partitioned with distilled water (DW), ethyl acetate (EtOAc), and n-butanol (n-BuOH). All extracts, as well as isolated biflavonoids from R. parviflora, were evaluated for their affinity to the benzodiazepine binding site of GABA_A receptor. The sedative-hypnotic effects of the fractions were evaluated by measuring sleep latency and sleep duration during pentobarbital-induced sleep in mice after oral administration of the extract fractions.

Results

Oral administration of RPME (125 mg/kg, 250 mg/kg, 500 mg/kg, and 1000 mg/kg) produced a dose-dependent decrease in sleep latency and an increase in sleep duration in mice treated with pentobarbital. The methanol extract produced a hypnotic effect that was fully blocked by ³H-Ro 15-1788 flumazenil (FLU). Further, among the solvent fractions, the ethyl acetate fraction exhibited significant activity. Among the isolated compounds, biflavonoids mesuaferrone B (1), rhusflavone (3), and agathisflavone (4) competitively inhibited FLU binding with a K_i of 0.280 渭M, 0.045 渭M, and 0.091 渭M, respectively. In addition, analysis of the sedative-hypnotic effects of rhusflavone, as well as those of the ethyl acetate, n-butanol, and distilled water fractions revealed that the modulation of both the ethyl acetate fraction and biflavonoid rhusflavone (3) are the most potent in inducing sleep.

Conclusion

The presence of conjugated ketone and C6-C8鈥?biflavonoid linkage in rhusflavone may be responsible for BZD-site of the GABA_A leading to decrease in sleep latency and increase sleep duration.