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 the presynaptic metabotropic glutamate receptor agonist, L-2-amino-4-phosphonobutyrate (L-AP4) was tested on the development of electrical kindling and in fully kindled animals. L-AP4 inhibited epileptogenesis at 10 nmol in 0.5 microl buffer, by preventing the increase in both seizure score and afterdischarge duration. The effects were reversible after withdrawal of the drug, with all treated animals subsequently progressing to the fully kindled state at the same rate as control animals. The same concentration of the drug was also effective when injected into fully kindled animals. It significantly decreased the mean seizure score by 88% (P < 0.005) and increased the mean generalized seizure threshold (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 dose-dependent manner. MPPG (10 nmol) inhibited the antiseizure activity 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 effect on generalized seizure activity, and it had no detectable influence on the normal rate of kindled epileptogenesis. During in vitro studies using a microsuperfusion method, L-AP4 inhibited depolarization-induced release of [3H]D-aspartate from rat cortical synaptosomes (IC50 125.1 microM) and decreased the depolarization-evoked uptake of 45Ca2+ in a dose-dependent manner. Both actions of L-AP4 were reduced by the selective antagonist MPPG. When applied alone MPPG (200 microM) had no detectable action on veratridine-evoked 45Ca2+ uptake by the synaptosomes. These results suggest the mechanisms by which presynaptically active glutamate receptor agonists block the development of the chronically 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.
Abdul-Ghani
A S
AS
Department of Biology and Biochemistry, Birzeit University, West-Bank, Israel.
Attwell
P J
PJ
Singh Kent
N
N
Bradford
H F
HF
Croucher
M J
MJ
Jane
D E
DE
D000409:Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000613:Aminobutyrates / Q000627:therapeutic use*; D000679:Amygdala / Q000187:drug effects; D000704:Analysis of Variance; D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D002132:Calcium Radioisotopes; D002540:Cerebral Cortex / Q000187:drug effects / Q000648:ultrastructure; D004353:Drug Evaluation, Preclinical; D004827:Epilepsy / Q000188:drug therapy*; D018690:Excitatory Amino Acid Agonists / Q000627:therapeutic use*; D007696:Kindling, Neurologic / Q000187:drug effects*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists*; D013574:Synaptosomes / Q000187:drug effects
D000613:Aminobutyrates; D000927:Anticonvulsants; D002132:Calcium Radioisotopes; D018690:Excitatory Amino Acid Agonists; D018094:Receptors, Metabotropic Glutamate; C101185:alpha-methyl-4-phosphonophenylglycine; C012729:2-amino-4-phosphonobutyric acid; D000409:Alanine