Betulin binds to gamma-aminobutyric acid receptors and exerts anticonvulsant action in mice.
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.
Muceniece
Ruta
R
University of Latvia, Faculty of Medicine, Sarlotes St. la, Riga, Lv-1001, Latvia. Ruta.Muceniece@lu.lv
Saleniece
Kristine
K
Rumaks
Juris
J
Krigere
Liga
L
Dzirkale
Zane
Z
Mezhapuke
Rudolfs
R
Zharkova
Olga
O
Klusa
Vija
V
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
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