ANTI-EPILEPTOGENIC AND ANTICONVULSANT ACTIVITY OF L-2-AMINO-4-PHOSPHONOBUTYRATE, A PRESYNAPTIC GLUTAMATE-RECEPTOR AGONIST

The protective effect of amygdaloid (focally administered) doses of th e presynaptic metabotropic glutamate receptor agonist, L-2-amino-4-pho sphonobutyrate (L-AP4) was tested on the development of electrical kin dling and in fully kindled animals. L-AP4 inhibited epileptogenesis at 10 nmol in 0.5 mu l buffer, by preventing the increase in both seizur e score and afterdischarge duration. The effects were reversible after withdrawal of the drug, with all treated animals subsequently progres sing to the fully kindled state at the same rate as control animals. T he same concentration of the drug was also effective when injected int o fully kindled animals, It significantly decreased the mean seizure s core by 88% (P<0.005) and increased the mean generalized seizure thres hold (GST) by 85% (P<0.005). The increase in GST was accompanied by a significant delay before the onset of generalized seizure and by a 37% reduction in generalized seizure duration. MPPG ((RS)-alpha-methyl-4- phosphonophenyl glycine) a selective antagonist of L-AP4 at glutamate pre-synaptic receptors inhibited the depressant effect of L-AP4 in a d ose-dependent manner. MPPG (10 nmol) inhibited the antiseizure activit y of L-Ap4, whilst MPPG (40 nmol) reduced both the anti-epileptogenic and antiseizure activities of L-AP4. MPPG (40 nmol) by itself had no e ffect on generalized seizure activity, and it had no detectable influe nce on the normal rate of kindled epileptogenesis. During in vitro stu dies using a microsuperfusion method, L-AP4 inhibited depolarization-i nduced release of [H-3]D-aspartate from rat cortical synaptosomes (IC5 0 125.1 mu M) and decreased the depolarization-evoked uptake of Ca-45( 2+) in a dose-dependent manner. Both actions of L-AP4 were reduced by the selective antagonist MPPG. When applied alone MPPG (200 mu M) had no detectable action on veratridine-evoked Ca-45(2+) uptake by the syn aptosomes. These results suggest the mechanisms by which presynaptical ly active glutamate receptor agonists block the development of the chr onically epileptic state induced by electrical kindling, and indicate that their anticonvulsive activity is due to inhibition of presynaptic glutamate and/or aspartate release following blockade of presynaptic Ca2+ entry.