Seizures induced by allylglycine, 3-mercaptopropionic acid and 4-deoxypyridoxine in mice and photosensitive baboons, and different modes of inhibition of cerebral glutamic acid decarboxylase.
1. DL-C-Allyglycine, 4-deoxypyridoxine hydrochloride and 3-mercaptopropionic acid have been studied with reference to their convulsant effects in mice and in baboons (Papio papio) with photosensitive epilepsy, and their action on the cerebral enzyme synthesizing gamma-aminobutyric acid (L-glutamate-1-carboxy-lyase).2. In mice, the ED(50) values for seizures following intraperitoneal injection were allylglycine 1.0 mmol/kg body weight, 4-deoxypyridoxine 1.1 mmol/kg and 3-mercaptopropionic acid 0.27 mmol/kg. Latency to seizure onset was longest after allylglycine (44-240 min), intermediate after 4-deoxypyridoxine (9-114 min) and shortest after 3-mercaptopropionic acid (2.5-8 min).3. In Papio papio intravenous administration of subconvulsant doses of allylglycine (0.87-3.1 mmol/kg), or of 4-deoxypyridoxine (0.21-0.53 mmol/kg) enhanced the occurrence and persistence of myoclonic responses to intermittent photic stimulation, and augmented the associated electroencephalographic abnormalities, without modifying their character or distribution. Higher doses produced brief seizures recurring at regular intervals, between 2-14 h after allylglycine (4.0-4.3 mmol/kg) or 1-4 h after 4-deoxypyridoxine (0.53-0.87 mmol/kg). Electroencephalographically these seizures originated unilaterally in the occipital or posterior parietal cortex.4. In Papio papio photically-induced epileptic responses were enhanced 5-10 min after the intravenous injection of 3-mercaptopropionic acid (0.09-0.28 mmol/kg). A sequence of brief generalized seizures followed by complete recovery occurred 4-17 min after the injection of 3-mercaptopropionic acid (0.28-0.38 mmol/kg). Fatal status epilepticus followed the injection of 3-mercaptopropionic acid (0.57-0.75 mmol/kg). E.E.G. records showed generalized cortical involvement at the onset of the seizures.5. L-Glutamate 1-carboxy-lyase (GAD) activity was determined in whole brain homogenates from mice killed at various intervals after receiving i.p. a convulsant dose of one of the compounds. Inhibition of GAD activity was evident 30-60 min before seizure onset following allylglycine or 4-deoxypyridoxine administration, and was maximal (40-60%) just before or during seizure activity. Addition of pyridoxal phosphate to the brain homogenate relieved inhibition produced by 4-deoxypyridoxine but not that produced by allylglycine. Inhibition of GAD activity in brain homogenates from animals killed 2 or 4 min after injection of a convulsant dose of 3-mercaptopropionic acid varied from 0-49% depending on the dose of 3-mercaptopropionic acid and the concentration of substrate in the assay system.6. Kinetic analysis of the inhibition of GAD activity following direct addition of the compounds to mouse brain homogenates indicated that 3-mercaptopropionic acid (0.01-0.5 mM) was competitive with respect to the substrate. A comparable percentage inhibition of GAD activity was obtained only with much higher concentrations of 4-deoxypyridoxne, i.e. 10-50 mM. Allylglycine in vitro was a very weak inhibitor of GAD activity.7. Three biochemically different mechanisms underlie the inhibition of cerebral GAD activity that precedes seizures induced by ailylglycine, 4-deoxypyridoxine and 3-mercaptopropionic acid. The data are consistent with a critical reduction in the rate of synthesis of gamma-aminobutyric acid being responsible for the onset of seizures.
D000498:Allyl Compounds / Q000633:toxicity; D000818:Animals; D001921:Brain / Q000201:enzymology*; D002262:Carboxy-Lyases / Q000037:antagonists & inhibitors*; D004569:Electroencephalography; D005971:Glutamates; D005998:Glycine / Q000633:toxicity*; D000882:Haplorhini; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007700:Kinetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D009207:Myoclonus / Q000139:chemically induced; D010215:Papio; D010775:Photic Stimulation; D011422:Propionates / Q000633:toxicity*; D011736:Pyridoxine / Q000633:toxicity*; D012640:Seizures / Q000139:chemically induced*; D013438:Sulfhydryl Compounds / Q000633:toxicity*; D013997:Time Factors
D000498:Allyl Compounds; D005971:Glutamates; D011422:Propionates; D013438:Sulfhydryl Compounds; D002262:Carboxy-Lyases; D011736:Pyridoxine; D005998:Glycine