Seizures induced by intracerebral administration of pyridoxal-5 '-phosphate: effect of GABAergic drugs and glutamate receptor antagonists

Pyridoxal-5'-phosphate (PLP), the cofactor of glutamate decarboxylase, para doxically induces convulsions when injected intracranially in adult mammals . We have tested the effect of some GABAergic and antiglutamatergic drugs o n the behavioral and electroencephalographic (EEG) seizures produced by int racerebroventricular (i.c.v.) microinjection of 1 mu mol PLP in the rat. PL P induced barrel turning, running fits and tonic-clonic convulsions, which started 5-10 min after recovery from the anesthesia (halothane), peaked at 20 min and disappeared at about 50 min. These symptoms were accompanied by frequent high amplitude EEG spike burst discharges. Pyridoxal, pyridoxamine -5'-phosphate or deoxypyridoxine were ineffective. The i.c.v. microinjectio n of the GABAergic compounds muscimol, isoguvacine, aminooxyacetic acid or GABA itself, significantly protected against PLP effects. In contrast, the NMDA receptor antagonists MK-801 and the non-NMDA receptor antagonist NBQX, failed to protect and induced motor alterations and mortality. We conclude that a temporary decrease of the GABA(A) receptor function is involved in the convulsant effect of PLP. This decrease might be due to the formation o f a Schiff base between the carbonyl group of PLP and the epsilon -amino gr oup of a functionally crucial lysine residue located in one extracellular l oop of the GABA(A) receptor. (C) 2001 Elsevier Science Ltd. All rights rese rved.