Excitatory amino acid antagonists and the anticonvulsive activity of conventional antiepileptic drugs.
There is a great body of evidence, that excitatory amino acid antagonists, apart from their anticonvulsive properties per se, potentiate the protective activity of conventional antiepileptics against maximal electroshock-induced seizures in mice. It is worth stressing, that combinations of valproate with either CGP 37849 (a competitive NMDA antagonist) or dizocilpine (MK-801, a non-competitive NMDA antagonist), providing a 50% protection against maximal electroshock, resulted in no adverse effects, as measured in the chimney test (motor coordination) or passive avoidance task (long-term memory). On the other hand, valproate administered alone at its ED50, to protect against maximal electroshock, produced profound adverse effects. However, some NMDA antagonists (D-CPP-ene, memantine, procyclidine or trihexyphenidyl) did enhance the protection offered by common antiepileptics but these combined treatments were associated with considerable side-effects on motor coordination and long-term memory. Interestingly, ifenprodil (an antagonist of the polyamine site within the NMDA receptor complex) possessed some anticonvulsive activity against electroconvulsions but failed to enhance the antielectroshock efficacy of conventional antiepileptics. AMPA/KA receptor antagonists (NBQX and GYKI 52466), similarly to NMDA antagonists, potentiated the protective action of antiepileptic drugs against maximal electroshock and these combinations were generally devoid of unwanted effects.
Kleinrok
Z
Z
Department of Pharmacology and Toxicology, Medical Academy, Lublin, Poland.
Turski
W A
WA
Czuczwar
S J
SJ
D000927:Anticonvulsants / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D004347:Drug Interactions; D018691:Excitatory Amino Acid Antagonists / Q000009:adverse effects / Q000494:pharmacology*; D018846:Excitatory Amino Acids / Q000009:adverse effects; D006801:Humans; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors / Q000494:pharmacology; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy*
D000927:Anticonvulsants; D018691:Excitatory Amino Acid Antagonists; D018846:Excitatory Amino Acids; D016202:N-Methylaspartate