Formation of GABOB from 2-hydroxyputrescine and its anticonvulsant effect.
To investigate the formation of gamma-amino-beta-hydroxybutyric acid from 2-hydroxyputrescine in mammalian organs, the radioactive diamine was synthesized and was injected into rats intraperitoneally or intraventricularly. After intraperitoneal injection, the radioactive amino acid was detected in various organs, but formation of the stereoisomer of the amino acid (gamma-amino-alpha-hydroxybutyric acid) was not demonstrated. Intraventricular injection of the radioactive diamine also resulted in the formation of gamma-amino-beta-hydroxybutyric acid in the rat brain. In vivo experiments using monoamine oxidase or diamine oxidase inhibitors suggested the participation of both enzymes in the formation of the amino acid from the diamine in rat organs other than the brain, where diamine oxidase appeared to play the major role. To investigate the anticonvulsant effect of 2-hydroxyputrescine, the threshold of pentylenetetrazol-induced generalized convulsions was measured in rats after the intraventricular injection of 2-hydroxyputrescine. Both R(-)- and S(+)-2-hydroxyputrescine had an anticonvulsant effect, with a greater elevation of the threshold being observed after injection of the R(-) form. Time course experiments suggested that this anticonvulsant effect depended on the formation of gamma-amino-beta-hydroxybutyric acid from 2-hydroxyputrescine in the rat brain. The anticonvulsant action of gamma-amino-beta-hydroxybutyric acid was also examined, and the stimulation of Cl- influx plus the inhibition of GABA uptake into brain membrane vesicles were indicated to be involved.
Nakao
J
J
Department of Neuropsychiatry, Kyoto Prefectural University of Medicine, Japan.
Hasegawa
T
T
Hashimoto
H
H
Noto
T
T
Nakajima
T
T
D000612:4-Aminobutyrate Transaminase / Q000032:analysis; D006631:Amine Oxidase (Copper-Containing) / Q000037:antagonists & inhibitors / Q000378:metabolism; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D000927:Anticonvulsants / Q000378:metabolism / Q000494:pharmacology*; D001923:Brain Chemistry / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism; D005968:Glutamate Decarboxylase / Q000378:metabolism; D007274:Injections, Intraperitoneal; D007276:Injections, Intraventricular; D008297:Male; D010433:Pentylenetetrazole; D011700:Putrescine / Q000031:analogs & derivatives* / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology
D000596:Amino Acids; D000927:Anticonvulsants; D002712:Chlorides; C004480:4-amino-3-hydroxybutyric acid; C002952:2-hydroxyputrescine; D005680:gamma-Aminobutyric Acid; D006631:Amine Oxidase (Copper-Containing); D000612:4-Aminobutyrate Transaminase; D005968:Glutamate Decarboxylase; D011700:Putrescine; D010433:Pentylenetetrazole