N-methyl-D-aspartate receptors contribute to guanidinosuccinate-induced convulsions in mice.
Increased levels of the endogenous convulsant guanidinosuccinate (GSA) might contribute to the epileptic symptomatology presenting in patients with renal failure. Little is known, however, about the underlying epileptogenic mechanism of guanidinosuccinate-induced convulsions. In this paper, we present pharmacological evidence for a direct excitatory action of this compound. In particular, the close involvement of N-methyl-D-aspartate (NMDA) receptors in the pathogenesis of GSA-induced generalized convulsions is suggested. GSA potentiated NMDA-induced convulsions significantly, but not L-glutamate- or kainate-induced convulsions. Conversely, and in addition, NMDA receptor antagonists, like D(-)-2-amino-5-phosphonovalerate, CGP 37849 [DL)-(E)-2-amino-4-methyl-5-phosphono-3-pentenoate] or ketamine (but not kynurenate), blocked the convulsions induced by i.c.v. injection of GSA dose dependently whereas anti-epileptic drugs, like carbamazepine, diazepam, phenobarbital or valproate, only abolished the tonic extension phase of these convulsions. Thus, NMDA receptors appear to be involved, at least partly, in GSA-induced convulsions.
D'Hooge
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Laboratory of Neurochemistry and Behavior, Born-Bunge Foundation, University of Antwerp, Belgium.
Pei
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De Deyn
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D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D004347:Drug Interactions; D005260:Female; D005971:Glutamates / Q000633:toxicity; D018698:Glutamic Acid; D006146:Guanidines / Q000633:toxicity*; D007608:Kainic Acid / Q000633:toxicity; D007649:Ketamine / Q000494:pharmacology; D007736:Kynurenic Acid / Q000494:pharmacology; D008297:Male; D051379:Mice; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000502:physiology*; D012640:Seizures / Q000139:chemically induced* / Q000503:physiopathology; D013386:Succinates / Q000633:toxicity*
D000927:Anticonvulsants; D005971:Glutamates; D006146:Guanidines; D016194:Receptors, N-Methyl-D-Aspartate; D013386:Succinates; C064539:2-amino-4-methyl-5-phosphono-3-pentenoic acid; D018698:Glutamic Acid; C001318:guanidinosuccinic acid; D007649:Ketamine; D015763:2-Amino-5-phosphonovalerate; D007736:Kynurenic Acid; D007608:Kainic Acid