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

Rhus parviflora is referred as ‘Tintidikah’ in traditional medicinal system of south Asia (Ayurveda). It is used in treatment of VÄta vikÄra, a condition related to neurological complications as well as cure for stomach disorders. 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. 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 Ki of 0.280 Î¼M, 0.045 Î¼M, and 0.091 Î¼M, 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. 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. Rhus parviflora Roxb. is a sub-deciduous native shrub of south Asia mentioned in traditional medicinal system of Ayurveda as Tintidikah. A biflavonoid rhusflavone from its fruits showed remarkable binding activity to GABA-BZD receptors. View high quality image (74K)