Gamma-vinyl GABA: comparison of neurochemical and anticonvulsant effects in mice.
Biochemical and pharmacological effects of gamma-vinyl GABA (Vigabatrin, GVG), and irreversible enzyme-activated inhibitor of 4-aminobutyrate: 2-oxoglutarate aminotransferase (EC 2.6.1.19; GABA-T), were measured in mice. This anticonvulsant produced a time- and dose-dependent elevation of the GABA, phenylalanine and lysine contents of cortical tissue and simultaneously decreased glutamate, aspartate and alanine levels. In addition, GVG caused a biphasic change in glutamine concentrations (a decline 1-4 hours after administration, followed 20 hours later by an increase). Moreover, we found a new, as yet unidentified amino acid in the brain eluting with the same retention time as alpha-aminoadipic acid from an HPLC cation-exchange column. The level of this novel chemical entity was greatly increased by GVG 20 hours after injection of the drug. At all tested intervals between 1 and 60 hours after injection, GVG was ineffective against maximal electroshock. The GABA-T inhibitor dose-dependently protected mice against isoniazid-induced seizures, simultaneously causing an increase in brain GABA concentrations. However, this apparent correlation applied only until 4 hours after treatment. To better define the anticonvulsant profile of GVG, groups of mice were treated, 1, 2, 4, and 24 hours prior to challenge with convulsant doses of strychnine, pentetrazole (PTZ), and picrotoxin, and brain amino acid levels, including brain concentrations of GVG, were measured. In all instances, the time dependency of the anticonvulsant effects of GVG and of increases in brain GABA levels differed. Amino acid concentrations in animals treated only with GVG were similar to those in animals given GVG and a chemical convulsant. GVG showed no selectivity for seizures produced by impairment of GABA-ergic neurotransmission. Although GVG is an effective GABA-T inhibitor, it apparently affects several other pyridoxal-phosphate-dependent cerebral enzymes and/or interacts with other neurotransmitter systems as well.
Biology Research Laboratories, Pharmaceuticals Division, Ciba-Geigy Ltd, Basle, Switzerland.
R
R
Bernasconi
M
M
Klein
P
P
Martin
P
P
Christen
T
T
Hafner
C
C
Portet
M
M
Schmutz
D000612:4-Aminobutyrate Transaminase / Q000037:antagonists & inhibitors; D000596:Amino Acids / Q000378:metabolism; D000614:Aminocaproates / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism; D007267:Injections; D007538:Isoniazid; D051379:Mice; D009994:Osmolar Concentration; D010433:Pentylenetetrazole; D010852:Picrotoxin; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy; D020888:Vigabatrin; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D000612:4-Aminobutyrate Transaminase; D000596:Amino Acids; D000614:Aminocaproates; D000927:Anticonvulsants; D007538:Isoniazid; D010433:Pentylenetetrazole; D010852:Picrotoxin; D020888:Vigabatrin; D005680:gamma-Aminobutyric Acid