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

Abstract

Summary 1. DL-C-Allylglycine, 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 y-aminobutyric acid (L-glutamate-1-carboxy-lyase).2. In mice, the EI)0 values for seizures following intraperitoneal injection were allylglycine 1-0 mmol/kg body weight, 4-deoxypyridoxine 141 mmol/kg and 3-mercaptopropionic acid 027 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 (0O87-3-1 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 (009-028 mmoi/kg). A sequence of brief generalized seizures followed bv 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 * Present address:

Cross-species pharmacological characterization of the allylglycine seizure model in mice and larval zebrafish

“…injection in mice versus bath exposure in zebrafish larvae), the time-course of GABA depletion in zebrafish matched with the residual activity of GAD estimated in mice previously by Horton and Meldrum [41] (at the dose of 200-mg/kg AG, in BALB/C mice, GAD activity dropped by about 35% of the initial values at 90 min post-AG injection followed by seizures in the span of 95-180 min post-AG dose). …”

“…This latency period was described previously in mice (44-240 min) and in rats (120-150 min) by Horton and Meldrum [41] and Alberici et al [64], respectively. A wide variation in seizure onset between test animals was also reported by these authors.…”

“…In zebrafish, convulsive behaviors were observed for the majority of larvae within 1.5 to 2 h of bathing in 300-mM AG. Similar to rodents, increasing the dose shortened the latency to death more than the latency to seizures [41].…”

“…Allylglycine has been reported to induce convulsions in rodents [37,41] and goldfish [42] and to enhance epileptic responses triggered by photic stimulation in baboons [41]. However, only a few studies were performed to correlate in vivo convulsive behavior with cerebral GABA and glutamate levels after AG injection [37][38][39].…”

Blockade of GABA synthesis only affects neural excitability under activated conditions in rat hippocampal slices

“…The degree of GAD inhibition seen in vivo and in the brain slice may depend on a variety factors; glutamate content would be critical because MPA inhibits GAD by competing with glutamate for the enzyme (Adcock and Taberner, 1978, Horton and Meldrum, 1973, Lamar, 1970. The intracellular glutamate content of GABAergic neurons controls the degree of GAD inhibition produced by MPA and could contribute to the partial (∼50%) inhibition reported consistently by studies of intact animal, cell culture and slice models including our own that used MPA concentrations 100-1000 fold greater the Ki of GAD.…”