De Deyn P P, Marescau B, MacDonald R L
Laboratory of Neurochemistry, Born-Bunge Foundation, U.I.A., Antwerp, Belgium.
Acta Neurol Belg. 1990;90(2):65-81.
A brief review is given with regard to the GABAergic alterations in experimental and genetic models of epilepsy and human epilepsy, illustrating, among others, that agents exist, both convulsants and anticonvulsants, that are capable of interacting with GABA's synthesis, storage, extraneuronal release, presynaptic reuptake, postsynaptic destruction and activation. The so-called "GABA-hypothesis" of epilepsy implies that a reduction of GABA-ergic inhibition results in epilepsy while an enhancement of GABAergic inhibition results in an antiepileptic effect. The examples presented, in support of the "GABA-hypothesis", concern the effects of some exogenous [pentylenetetrazol (PTZ) and methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM)] and some endogenous convulsants on the postsynaptic GABAA receptor. The studied endogenous convulsants were the guanidino compounds which are known to increase in uremia and hyperargininemia. PTZ and DMCM dose-dependently reduced GABA responses on mouse neurons in cell culture. The benzodiazepine receptor antagonist CGS 9896 antagonized the DMCM- but not the PTZ-induced inhibition of GABA-responses. The guanidino compounds guanidine, methylguanidine, creatinine, guanidinosuccinic acid (increased in uremia) and arginine, homoarginine, alpha-keto-delta-guanidinovaleric acid and argininic acid (increased in hyperargininemia) decreased both GABA- and GLY-responses. The guanidino compounds were equally potent in decreasing GABA- and GLY-responses and CGS 9896 did not antagonize the guanidino compound-induced inhibition of GABA responses. The presented results indicate that the studied convulsants inhibit GABAergic inhibition through interaction with distinct sites at the postsynaptic GABAA receptor. The demonstrated effect might, in agreement with the "GABA-hypothesis", underlie the epileptogenicity of these compounds in animal models and might have pathophysiological importance in uremia and hyperargininemia.
本文简要回顾了癫痫实验模型、遗传模型及人类癫痫中的γ-氨基丁酸（GABA）能改变，其中特别指出，存在一些惊厥剂和抗惊厥剂，它们能够与GABA的合成、储存、神经元外释放、突触前再摄取、突触后破坏及激活相互作用。癫痫的所谓“GABA假说”意味着，GABA能抑制作用减弱会导致癫痫，而GABA能抑制作用增强则会产生抗癫痫效果。为支持“GABA假说”所列举的例子，涉及一些外源性物质[戊四氮（PTZ）和6,7-二甲氧基-4-乙基-β-咔啉-3-羧酸甲酯（DMCM）]及一些内源性惊厥剂对突触后GABAA受体的影响。所研究的内源性惊厥剂为胍基化合物，已知其在尿毒症和高精氨酸血症时会增加。PTZ和DMCM在细胞培养中对小鼠神经元的GABA反应呈剂量依赖性降低。苯二氮䓬受体拮抗剂CGS 9896可拮抗DMCM诱导的GABA反应抑制，但不能拮抗PTZ诱导的抑制。胍基化合物胍、甲基胍、肌酸酐、胍基琥珀酸（在尿毒症时增加）以及精氨酸、高精氨酸、α-酮-δ-胍基戊酸和精氨酸酸（在高精氨酸血症时增加）均降低了GABA和甘氨酸（GLY）反应。胍基化合物在降低GABA和GLY反应方面具有同等效力，且CGS 9896不能拮抗胍基化合物诱导的GABA反应抑制。所呈现的结果表明，所研究的惊厥剂通过与突触后GABAA受体的不同位点相互作用来抑制GABA能抑制。与“GABA假说”一致，所证明的这种作用可能是这些化合物在动物模型中致痫性的基础，并且在尿毒症和高精氨酸血症中可能具有病理生理学意义。
