Main content area

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

Shrestha, Sabina, Park, Ji-Hae, Lee, Dae-Young, Cho, Jin-Gyeong, Cho, Suengmok, Yang, Hye-Jin, Yong, Hye-Im, Yoon, Min-Seok, Han, Dae-Seok, Baek, Nam-In
Journal of ethnopharmacology 2012 v.142 no.1 pp. 213-220
Ayurvedic medicine, Rhus, acetates, binding sites, fruits, ketones, methanol, mice, oral administration, pentobarbital, receptors, sleep, stomach
ETHNOPHARMACOLOGICAL RELEVANCE: Rhus parviflora is referred as ‘Tintidikah’ in traditional medicinal system of south Asia (Ayurveda). It is used in treatment of Vāta vikāra, 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 GABAA 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 (125mg/kg, 250mg/kg, 500mg/kg, and 1000mg/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 Kᵢ of 0.280μM, 0.045μM, and 0.091μM, 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″ biflavonoid linkage in rhusflavone may be responsible for BZD-site of the GABAA leading to decrease in sleep latency and increase sleep duration.