title: Convulsant activity of pyridoxal sulphate and phosphonoethyl pyridoxal: antagonism by GABA and its synthetic analogues.
abstract: 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 (mumol/10 microliters/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 CH2NH2 or CH2OH 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 PO4, CHO and CH2--CH2PO2-4 but especially CHO and --OSO23-- groups. This seizure activity was prevented, attenuated or reversed by intracerebroventricular administration of 20 microliter of GABA (1 mumol), muscimol (0.025 mumol), trans-4-aminocrotonic acid (0.25 mumol), isoguvacine (0.25 mumol) or THIP (0.25 mumol), 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.
mesh_terms: D000612:4-Aminobutyrate Transaminase / Q000378:metabolism; D000818:Animals; D000927:Anticonvulsants; D001923:Brain Chemistry / Q000187:drug effects; D003292:Convulsants; D005968:Glutamate Decarboxylase / Q000378:metabolism; D007276:Injections, Intraventricular; D008297:Male; D011730:Pyridoxal / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D011731:Pyridoxal Kinase / Q000378:metabolism; D011732:Pyridoxal Phosphate / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*
chemical_list: D000927:Anticonvulsants; D003292:Convulsants; C039020:5-(2-phosphonoethyl)pyridoxal; D011730:Pyridoxal; D005680:gamma-Aminobutyric Acid; D011732:Pyridoxal Phosphate; D000612:4-Aminobutyrate Transaminase; D011731:Pyridoxal Kinase; D005968:Glutamate Decarboxylase