title: Betulin binds to gamma-aminobutyric acid receptors and exerts anticonvulsant action in mice.
abstract: The lupane type pentacyclic triterpenes: lupeol, betulin, and betulinic acid are widely distributed natural compounds. Recently, pharmaceutical compositions from plant extracts (family Marcgraviaceae) containing betulinic acid, have been patented as anxiolytic remedies. To extend our knowledge of the CNS effects of the triterpenes, we suggest here that the chemically related lupeol, betulin and betulinic acid may interact with the brain neurotransmitter gamma-aminobutyric acid (GABA) receptors in vitro and in vivo. Using radioligand receptor-binding assay, we showed that only betulin bound to the GABA(A)-receptor sites in mice brain in vitro and antagonised the GABA(A)-receptor antagonist bicuculline-induced seizures in mice after intracisternal and intraperitoneal administration. Neither betulinic acid nor lupeol bound to GABA(A) receptor nor did they inhibit bicuculline-induced seizures in vivo. These findings demonstrate for the first time the CNS effects of betulin in vivo, and they also show distinct GABA(A)-receptor-related properties of lupane type triterpenes. These findings may open new avenues in understanding the central effects of betulin, and they also indicate possibilities for novel drug design on the basis of betulin structure.
authors.affiliation: University of Latvia, Faculty of Medicine, Sarlotes St. la, Riga, Lv-1001, Latvia. Ruta.Muceniece@lu.lv
authors.forename: Ruta
authors.initials: R
authors.lastname: Muceniece
authors.forename: Kristine
authors.initials: K
authors.lastname: Saleniece
authors.forename: Juris
authors.initials: J
authors.lastname: Rumaks
authors.forename: Liga
authors.initials: L
authors.lastname: Krigere
authors.forename: Zane
authors.initials: Z
authors.lastname: Dzirkale
authors.forename: Rudolfs
authors.initials: R
authors.lastname: Mezhapuke
authors.forename: Olga
authors.initials: O
authors.lastname: Zharkova
authors.forename: Vija
authors.initials: V
authors.lastname: Klusa
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000927:Anticonvulsants / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology*; D001640:Bicuculline / Q000494:pharmacology; D005445:Flunitrazepam / Q000378:metabolism; D018757:GABA Modulators / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009129:Muscle Tonus / Q000187:drug effects; D053978:Pentacyclic Triterpenes; D004856:Postural Balance / Q000187:drug effects; D018079:Receptors, GABA / Q000378:metabolism*; D012640:Seizures / Q000139:chemically induced / Q000523:psychology; D014315:Triterpenes / Q000378:metabolism* / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism; D000094062:Betulinic Acid; D000094042:Lupanes
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000927:Anticonvulsants; D000970:Antineoplastic Agents; D001640:Bicuculline; D005445:Flunitrazepam; D018757:GABA Modulators; D053978:Pentacyclic Triterpenes; D018079:Receptors, GABA; D014315:Triterpenes; D005680:gamma-Aminobutyric Acid; D000094062:Betulinic Acid; C002503:betulin; C010480:lupeol; D000094042:Lupanes