Antagonism of N-methyl-D,L-aspartic acid-induced convulsions by antiepileptic drugs and other agents

The effects of common antiepileptics, GABAmimetic drugs, excitatory amino acid antagonists as well as of clonidine, corynanthine, chlorpromazine and atropine were studied against clonic convulsions induced in mice by N-methyl-D,L-aspartic acid (NMDLA) after subcutaneous (340 mg/kg; ED97) and intravenous (105 mg/kg; ED97) administration. Among the antiepileptics studied, valproate (ED50: 340 mg/kg after subcutaneous injection of NMDLA) and diazepam (ED50: 0.78 mg/kg after intravenous and 14 mg/kg after subcutaneous injection of NMDLA) antagonized NMDLA-induced convulsions, whereas phenobarbital (up to 80 mg/kg), diphenylhydantoin (up to 50 mg/kg) and ethosuximide (500 mg/kg) were totally ineffective. Moreover, 2-amino-5-phosphonopentanoic acid and 2-amino-7-phosphonoheptanoic acid (but not glutamic acid diethyl ester), aminooxyacetic acid, cetyl GABA and clonidine protected strongly against the convulsant whereas progabide was only weakly active. THIP showed a higher activity against intravenous than against subcutaneous NMDLA. Baclofen and atropine even increased mortality and the remaining agents exerted no significant protective action. The data suggest that NMDLA-induced convulsions can be blocked effectively by direct antagonism of NMDLA-produced excitation, enhancement of GABA-mediated inhibition, and activation of central alpha 2-adrenoceptors. The possible efficacy of valproate in cases of epilepsy with a distinct rise in plasma excitatory amino acid levels should be carefully considered.