Anticonvulsant properties of non-competitive antagonists of the N-methyl-D-aspartate receptor in genetically epilepsy-prone rats: comparison with CPPene.
Some non-competitive antagonists of N-methyl-D-aspartate (NMDA) were evaluated for potency to antagonize audiogenic seizures in genetically epilepsy-prone rats, following intraperitoneal administration. Phencyclidine (PCP), dizocilpine (MK-801), ketamine, ifenprodil and dextromethorphan, displayed anticonvulsant activity at doses similar to those which impaired performance in the rotarod equilibrium procedure. The noncompetitive NMDA receptor antagonists, at doses which slightly overlapped with the doses required for a full anticonvulsant protection against audiogenic seizures in genetically epilepsy-prone rats, induced profound untoward behavioural effects. This behavioural syndrome was characterized by marked ataxia, hyperactivity, stereotypes and wet dog shakes. In contrast, the effective anticonvulsant dose of 3-(2-carboxypiperazin-4-yl)propenyl-1-phosphonic acid (CPPene) was less than that required to impair rotarod performance and did not produce the PCP-like syndrome. A potential use in antiepileptic therapy, of CPPene or other new selective NMDA antagonists, with fewer neurotoxic effects but not for non-competitive antagonists such as MK-801, is suggested.
De Sarro
G B
GB
Department of Experimental Medicine, Faculty of Medicine, Catanzaro, University of Reggio Calabria, Italy.
De Sarro
A
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D000161:Acoustic Stimulation; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology / Q000633:toxicity; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology* / Q000633:toxicity; D003915:Dextromethorphan / Q000494:pharmacology / Q000633:toxicity; D016291:Dizocilpine Maleate / Q000494:pharmacology / Q000633:toxicity; D004827:Epilepsy / Q000235:genetics / Q000517:prevention & control*; D007274:Injections, Intraperitoneal; D007649:Ketamine / Q000494:pharmacology / Q000633:toxicity; D008297:Male; D009068:Movement / Q000187:drug effects; D010622:Phencyclidine / Q000494:pharmacology / Q000633:toxicity; D010879:Piperazines / Q000494:pharmacology* / Q000633:toxicity; D010880:Piperidines / Q000494:pharmacology / Q000633:toxicity; D004856:Postural Balance / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
D000317:Adrenergic alpha-Antagonists; D000927:Anticonvulsants; D010879:Piperazines; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; C065286:SDZ EAA 494; D007649:Ketamine; D016291:Dizocilpine Maleate; D003915:Dextromethorphan; D010622:Phencyclidine; C010739:ifenprodil