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Neurochemical and neurophysiological mechanism for guanidino compoundinduced seizures

胍基化合物诱发癫痫发作的神经化学和神经生理学机制

基本信息

批准号：
58440081
负责人：
MORI Akitane
金额：
$ 10.05万
依托单位：
Okayama University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (A)
财政年份：
1983
资助国家：
日本
起止时间：
1983 至 1985
项目状态：
已结题

项目摘要

We have reported that guanidino compound, e.g. taurocyamine, guanidinoacetic acid, <gamma> -guanidinobutyric acid, N-acetylarginine, methylguanidine, and <alpha> -guanidinoglutaric acid(GGA), induced violent convulsions after intracisternal injection into rabbits, dogs, cats, and rats. The summary of the present studies is as follows:1. Increased levels of methylguanidine were observed in the cerebral cortex, cerebellum, midbrain, and medulla oblongata of El mice with a convulsive disposition. N-Acetylaspartic acid induced in the brain during convulsions.2. Increased levels of <gamma> -guanidinoacetic acid were observed in the rabbit CSF during pentylenetetrazol induced convulsions.3. GGA induced seizures were associated with an abnormal serotonergic function, i.e. the transitorily decreased level and facilitated release of 5-HT in the brain.4. Homoarginine and <alpha> -guanidinovaleric acid induced seizure discharges in rats, when administered topically or intracisternally. <alpha> -guanidinovaleric acid may act on a GABA system to induce spike discharges as an antagonist.5. Taurocyamine has bipolar effects on convulsions; i.e. it delayed markedly the dibenzoylguanidine-induced convulsions in mice. On the other hand, it increased the incidence of convulsion in the non-stimulated El-mice.6. A new guanidino compound, <alpha> -guanidinoethanol, was found in normal human urine. It induced epileptic EEG discharges and convulsions when administerd into the rat brain.7. Incoporation of a <^(15)N> into guanidinoacetic acid in the brain and kidney, and guanidinoacetic acid, methylguanidine and guanidinosuccinic acid in the liver, was observed with a <^(15)N> -analyser after the administration of L-(amidino- <^(15)N> -arginine into mice.8. A high level of taurocyamine was found in the CSF of epileptic patients. Higher levels of taurocyamine, methylguanidine and N-acetylarginine were demonstrated in the epileptogenic focus tissue of human epileptic patients.

我们已报道，在兔、狗、猫和大鼠脑池内注射的胍基化合物，如牛磺氰胺、胍基乙酸、伽马氨基丁酸、N-乙酰精氨酸、甲基胍和&lt；α&gt；-胍基戊二酸(GGA)，均可引起剧烈的惊厥。本研究的主要结论如下：1.惊厥倾向的EL小鼠大脑皮层、小脑、中脑和延髓中甲基胍水平升高。结论：1.惊厥时脑内N-乙酰天冬氨酸含量升高。在戊四氮诱发惊厥过程中，兔脑脊液中~lt；γ&Gt；-胍基乙酸水平升高。GGA诱导的癫痫发作与5-羟色胺能功能异常有关，即一过性脑内5-羟色胺水平降低，促进5-羟色胺的释放。高精氨酸和α-胍基戊酸在局部或脑室内给药时可诱导大鼠惊厥放电。&lt；α&gt；-鸟嘌呤戊酸可能作为拮抗剂作用于GABA系统以诱导放电。牛磺酸氰胺对小鼠惊厥有双极作用，即能显著延缓二苯甲酰胍诱发的小鼠惊厥。另一方面，增加了非刺激性EL-小鼠惊厥的发生率。在正常人尿液中发现了一种新的胍基化合物--α-胍基乙醇。给大鼠脑内注射后，可诱发癫痫样脑电放电和惊厥。给小鼠灌胃L-(15)N&gt；-精氨酸后，用~(15)N&gt；-分析仪观察到脑组织和肾脏中α&(15)N&gt；在脑组织和肾脏中转化为胍基乙酸，在肝脏中转化为胍基乙酸、甲基胍和胍基丁二酸。癫痫患者脑脊液中有较高水平的牛磺酸胞胺。在人类癫痫患者的致痫灶组织中，牛磺氰胺、甲基胍和N-乙酰精氨酸含量较高。