Effect of elevated brain GABA concentrations on the actions of bicuculline and picrotoxin in mice.

gamma-Acetylenic GABA and gamma-vinyl GABA, two catalytic irreversible inhibitors of mammalian brain GABA transaminase that produce several-fold increases in brain GABA concentrations were tested for their effects on bicuculline and picrotoxin-induced seizures and mortality in mice. Neither inhibitor influenced the frequency of seizures or death produced by either bicuculline or picrotoxin. Both inhibitors, however, produced a dose-dependent prolongation of the time to onset of seizures and death induced by picrotoxin but by bicuculline. These results suggest differences in the antagonism by bicuculline and picrotoxin of GABA-mediated neural functions.

Audiogenic seizure protection by elevated brain GABA concentration in mice: effects of gamma-acetylenic gaba and gamma-vinyl GABA, two irreversible GABA-T inhibitors.

gamma-Acetylenic GABA and gamma-vinyl GABA, two catalytic irreversible inhibitors of GABA-transaminase, produce marked and sustained elevations in mouse brain GABA concentrations and protect DBA/2 mice against audiogenically induced seizures in a similar dose and time-dependent manner. The acetylenic analog also inhibits GAD activity while the vinyl compound has minimal activity against this enzyme. The increase in brain GABA concentrations induced by these compounds correlates well with attenuation of audiogenic seizure intensity (r = 0.991 and 0.962 for gamma-acetylenic and gamma-vinyl GABA respectively) and with degree of seizure protection (r = 0.974 and 0.834). Seizure intensity is reduced by 50% when brain GABA is increased to 265% and 264% of control values by the two inhibitors and seizure incidence is halved at 322% and 324%. Thus, audiogenic seizure protection in genetically susceptible mice is apparently a function of whole brain GABA concentrations.

Antiseizure activity of gamma-acetylenic gamma-aminobutyric acid: a catalytic irreversible inhibitor of gamma-aminobutyric acid transaminase.

gamma-Acetylenic gamma-aminobutyric acid (gamma-acetylenic GABA) produces several-fold sustained elevations of brain GABA concentrations when administered intraperitoneally to mice. It protects mice against seizures induced by audiogenic stimuli, electroshock, thiosemicarbazide, isoniazid and strychnine. The duration and degree of audiogenic seizure protection appears to correlate with elevations in whole brain GABA levels. gamma-Acetylenic GABA does not protect against seizures induced by pentylenetetrazol or picrotoxin even at doses that increase brain GABA concentrations approximately 6-fold. This differential antiseizure activity suggests that the GABA system may play a role in some, but not all experimentally produced seizures.

Effect of GABA-transminase inhibition on rectal temperature in mice.

gamma-Acetylenic GABA (amino-4-hex-5-ynoic acid) and gamma-vinyl GABA (amino-4-hex-5-enoic acid), two catalytic irreversible inhibitors of GABA-transaminase, produce marked sustained elevations in brain GABA concentrations. Associated with these biochemical changes is a decrease in the rectal temperature of mice. This hypothermia can be reversed by increasing ambient temperature. The results suggest GABA plays an important role in mammalian central thermoregulation.

Blockade by metal complexing agents and by catalase of the effects of arachidonic acid on platelets: relevance to the study of anti-inflammatory mechanisms.

Metal-chelating agents inhibited platelet aggregation and the accompanying generation of rabbit aorta contracting and PG-like activities, when platelets were challenged with arachidonic acid. Inhibition required the presence of the chelating agents in the medium, and was insured by reagents avid for free or protein-bound copper. Catalase also prevented aggregation and generation of pharmacologically active substances; its activity was reversed by aminothiol agents and by Cu2+ and Zn2+, shown previously to potentiate the platelet effects of arachidonic acid. Inhibition by indomethacin was not prevented by amino-thiol drugs nor by Cu2+ or Zn2+. The catalase-induced inhibition was not affected by scavenging of thiol groups; this rules out, as a mechanism of action of catalase, the increased destruction of popoperoxides by glutathione peroxidase, which requires reduced glutathione as hydrogen donor. The results are compatible with the hypothesis that the agent that mediates platelet aggregation by arachidonic acid is a popoperoxide, requiring the presence either of H2O2 or of a similarly catalase-sensitive substance to be generated.