The effect of omega-phosphono-alpha-aminocarboxylic acids on seizures and brain amino acid levels in E1 mice.

The omega-phosphono-alpha-aminocarboxylic acids, e.g., 2-amino-5-phosphonopentanoate and 2-amino-7-phosphonoheptanoate, are known to act as potent and selective antagonists at N-methyl-D-aspartate receptors and to have a pronounced anticonvulsant action on a variety of animal models of epilepsy. In the present study, the effects of these omega-phosphono-alpha-aminocarboxylic acids on E1 mice were investigated. These mice are inbred mutant epileptic mice, which are highly susceptible to convulsive seizures upon throwing stimulation. 2-Amino-3-phosphonopropionate injected intraventricularly (at a dose of 1.04 mumol) had a marked anticonvulsant action, but at a lower dose (0.1 mumol), it induced running fits. 2-Amino-4-phosphonobutyrate induced transitory excitation just after the injection, followed by sedation. 2-Amino-5-phosphonopentanoate induced marked behavioral sedation. 2-Amino-6-phosphonohexanoate induced tonic-clonic convulsions and epileptic discharges in electroencephalograms. 2-Amino-7-phosphonoheptanoate showed a strong anticonvulsant action at a dose of 1.27 mumol, but it induced myoclonic seizures at a lower dose. Amino acid analyses of E1 mouse brain showed that 2-amino-3-phosphonopropionate increased the glutamine level, 2-amino-4-phosphonobutyrate decreased the aspartic acid level, 2-amino-5-phosphonopentanoate decreased the glutamic acid level, 2-amino-6-phosphonohexanoate decreased the glutamic acid, glutamine, gamma-aminobutyric acid, glycine and alanine levels, and 2-amino-7-phosphonoheptanoate decreased the glutamic acid label 1 hour after their injection. These findings suggest that the effects of omega-phosphono-alpha-aminocarboxylic acids on the E1 mouse brain are multiple and complicated, depending on the numbers of their carbon chain.