Epilepsy and the GABA-hypothesis a brief review and some examples.
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.
De Deyn
P P
PP
Laboratory of Neurochemistry, Born-Bunge Foundation, U.I.A., Antwerp, Belgium.
Marescau
B
B
MacDonald
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RL
D000818:Animals; D001921:Brain / Q000378:metabolism*; D002243:Carbolines / Q000494:pharmacology; D003292:Convulsants / Q000494:pharmacology; D004827:Epilepsy / Q000378:metabolism*; D018756:GABA Antagonists; D006146:Guanidines / Q000494:pharmacology; D006801:Humans; D051379:Mice; D010433:Pentylenetetrazole / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000096:biosynthesis / Q000378:metabolism*
D002243:Carbolines; D003292:Convulsants; D018756:GABA Antagonists; D006146:Guanidines; D011720:Pyrazoles; D011963:Receptors, GABA-A; C034818:methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate; D005680:gamma-Aminobutyric Acid; C034704:2-(4-chlorophenyl)-2,5-dihydropyrazolo(4,3-c)quinoline-3(3H)-one; D010433:Pentylenetetrazole