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
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
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DOI：
10.1111/j.1476-5381.1973.tb08267.x
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发表时间：
1973-01-01
影响因子：
7.3
通讯作者：
MELDRUM, BS
中科院分区：
文献类型：
--
作者：
HORTON, RW;MELDRUM, BS
已经研究了 1dl-C-烯丙基甘氨酸、4-脱氧吡哆醇盐酸盐和 3-巯基丙酸对患有光敏性癫痫的小鼠和狒狒 (Papio papio) 的惊厥作用，以及它们对合成 γ-氨基丁酸（l-谷氨酸-1-羧基裂解酶）的脑酶的作用。2在小鼠中，癫痫发作的 ED50 值腹腔注射烯丙基甘氨酸1·0 mmol/kg体重、4-脱氧吡哆醇1·1 mmol/kg和3-巯基丙酸0·27 mmol/kg。烯丙基甘氨酸后癫痫发作潜伏期最长（44-240 分钟），4-脱氧吡哆醇后潜伏期最长（9-114 分钟），3-巯基丙酸后最短（2·5-8 分钟）。3InPapio papio 静脉注射亚惊厥剂量的烯丙基甘氨酸（0·87-3·1 mmol/kg）或 4-脱氧吡哆醇(0·21–0·53 mmol/kg) 增强了对间歇性光刺激的肌阵挛反应的发生和持续性，并增强了相关的脑电图异常，但不改变其特征或分布。较高剂量会产生定期复发的短暂癫痫发作，在烯丙基甘氨酸（4·0–4·3 mmol/kg）后2-14小时或4-脱氧吡哆醇（0·53–0·87 mmol/kg）后1-4小时之间。脑电图显示，这些癫痫发作起源于单侧枕叶或后顶叶皮质。4在狒狒中，静脉注射 3-巯基丙酸 (0·09–0·28 mmoi/kg) 5–10 分钟后，狒狒诱发的癫痫反应增强。注射 3-巯基丙酸 (0·28–0·38 mmol/kg) 后 4–17 分钟发生一系列短暂的全身性癫痫发作，随后完全恢复。注射3-巯基丙酸（0·57–0·75 mmol/kg）后出现致命性癫痫持续状态。脑电图记录显示癫痫发作时全身皮质受累。在接受腹膜内注射后以不同时间间隔处死的小鼠的全脑匀浆中测定了 5l-谷氨酸 1-羧基裂解酶 (GAD) 活性。其中一种化合物的惊厥剂量。给予烯丙基甘氨酸或 4-脱氧吡哆醇后，GAD 活性在癫痫发作前 30-60 分钟明显受到抑制，并且在癫痫发作前或癫痫发作期间达到最大（40-60%）。在脑匀浆中添加磷酸吡哆醛可以缓解 4-脱氧吡哆醇产生的抑制作用，但不能缓解烯丙基甘氨酸产生的抑制作用。注射惊厥剂量的 3-巯基丙酸 2 或 4 分钟后，处死动物的脑匀浆中 GAD 活性的抑制范围为 0-49%，具体取决于 3-巯基丙酸的剂量和测定系统中底物的浓度。6直接将化合物添加到小鼠脑匀浆中后对 GAD 活性的抑制的动力学分析表明，3-巯基丙酸 (0·01–0·5 mm）相对于基材而言具有竞争力。只有使用更高浓度的 4-脱氧吡哆醇（即 10-50 mm）才能获得相当的 GAD 活性抑制百分比。烯丙基甘氨酸在体外是一种非常弱的 GAD 活性抑制剂。7 三种不同的生化机制是在烯丙基甘氨酸、4-脱氧吡哆醇和 3-巯基丙酸诱导癫痫发作之前抑制大脑 GAD 活性的基础。这些数据与导致癫痫发作的 γ-氨基丁酸合成速率的严重降低一致。
1dl‐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 γ‐aminobutyric acid (l‐glutamate‐1‐carboxy‐lyase).2In mice, the ED50values 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).3InPapio papiointravenous 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.4InPapio papiophotically‐induced epileptic responses were enhanced 5–10 min after the intravenous injection of 3‐mercaptopropionic acid (0·09–0·28 mmoi/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.5l‐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.6Kinetic 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‐deoxypyridoxine, i.e. 10–50 mm. Allylglycinein vitrowas a very weak inhibitor of GAD activity.7Three biochemically different mechanisms underlie the inhibition of cerebral GAD activity that precedes seizures induced by allylglycine, 4‐deoxypyridoxine and 3‐mercaptopropionic acid. The data are consistent with a critical reduction in the rate of synthesis of γ‐aminobutyric acid being responsible for the onset of seizures.