Excitatory Amino Acid Antagonists as Novel Anticonvulsants

Abstract

The convulsant effect of application of dicarboxylic amino acids to the cortex was first reported by Hayashi (1954). This observation suggests that antagonists of excitation induced by amino acid neurotransmitters might be anticonvulsant agents in some forms of epilepsy. Some rather weak and indeterminate anticonvulsant effects of glutamic acid diethyl ester were initially described (Freed and Michaelis, 1978; Freed, 1985). However, following the identification of potent and specific excita- tory amino acid antagonists (Davies et al., 1982) it was shown that compounds that selectively antagonized excitation at the N-methyl-D-aspartate preferring receptor are anticonvulsant, with a potency matching that of the benzodiazepines when administered intracerebroventricularly (Croucher et al., 1982; Chapman et al., 1984). Testing in a wide range of animal models shows that NMDA antagonists provide a novel class of anticonvulsant agent with a broad spectrum of activity roughly equivalent to that of sodium valproate when administered systemically. The further observation that they can protect against ischemic brain damage has strengthened the concept that an excitotoxic mechanism is involved in such damage (Meldrum et al., 1982; Simon et al., 1984).