Convulsant activity of pyridoxal sulphate and phosphonoethyl pyridoxal: Antagonism by GABA and its synthetic analogues

Pyridoxal phosphate and its synthetic analogues—pyridoxal 5'-sulphate and the 5-phosphonoethyl analogue of pyridoxal (phosphonoethyl pyridoxal) in doses of 0.125–0.250 (μmol/10μl/i.c.v./rat),caused epileptic seizures characterized by running fits, vocalization, muscular fasciculation and tonic-clonic convulsions. These effects were specific and could not be demonstrated with 5'-deoxypyridoxal, N-methylpyridoxal phosphate or the 5- trans-carboxyethenyl analogue of pyridoxal phosphate (carboxyethenyl pyridoxal). Structure-activity relationships of these analogues indicated that the presence of a CHO in position 4 of the pyridine ring was essential, since its conversion to CH 2NH 2 or CH 2OH abolished activity. The presence of an unsubstituted N was essential, since convulsions did not occur with N-methylpyridoxal phosphate. The presence of the hydroxyl group in position 5' was essential since 5'-deoxypyridoxal was inactive. The convulsive activity was potentiated in the presence of both CHO and PO 4 CHO and CH 2—CH 2PO 2− 4but especially CHO and — OSO 2− 3- groups. This seizure activity was prevented, attenuated or reversed by intracerebroventricular administration of 20 μ1 of GABA (1 μmol), muscimol (0.025 μmol), trans-4-aminocrotonic acid (0.25 μmol), isoguvacine (0.25 μmol) or THIP (0.25 μmol), but not by biogenic amines. An understanding of the mechanism of pyridoxal phosphate-related seizures may provide additional insights not only about GABA receptor sites but also about the biochemical manifestation and expression of epilepsy.