title: Rhus parviflora and its biflavonoid constituent, rhusflavone, induce sleep through the positive allosteric modulation of GABA(A)-benzodiazepine receptors.
abstract: BACKGROUND
  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.
  
  
  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 μM, 0.045 μM, and 0.091 μM, 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.
  
  
  CONCLUSIONS
  The presence of conjugated ketone and C6-C8″ biflavonoid linkage in rhusflavone may be responsible for BZD-site of the GABA(A) leading to decrease in sleep latency and increase sleep duration.
authors.affiliation: Graduate School of Biotechnology, Institute of Life Sciences and Resources, Kyung Hee University, Yongin 446-701, Republic of Korea.
authors.forename: Sabina
authors.initials: S
authors.lastname: Shrestha
authors.forename: Ji-Hae
authors.initials: JH
authors.lastname: Park
authors.forename: Dae-Young
authors.initials: DY
authors.lastname: Lee
authors.forename: Jin-Gyeong
authors.initials: JG
authors.lastname: Cho
authors.forename: Suengmok
authors.initials: S
authors.lastname: Cho
authors.forename: Hye-Jin
authors.initials: HJ
authors.lastname: Yang
authors.forename: Hye-Im
authors.initials: HI
authors.lastname: Yong
authors.forename: Min-Seok
authors.initials: MS
authors.lastname: Yoon
authors.forename: Dae-Seok
authors.initials: DS
authors.lastname: Han
authors.forename: Nam-In
authors.initials: NI
authors.lastname: Baek
mesh_terms: D000818:Animals; D044946:Biflavonoids / Q000032:analysis / Q000378:metabolism / Q000494:pharmacology*; D005638:Fruit; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010936:Plant Extracts / Q000032:analysis / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000502:physiology*; D029045:Rhus; D012890:Sleep / Q000187:drug effects* / Q000502:physiology
chemical_list: D044946:Biflavonoids; D006993:Hypnotics and Sedatives; D010936:Plant Extracts; D011963:Receptors, GABA-A