Kynurenine and probenecid inhibit pentylenetetrazol- and NMDLA-induced seizures and increase kynurenic acid concentrations in the brain.
Kynurenine is a direct precursor of kynurenic acid, the only known endogenous antagonist of excitatory amino acid receptors in the brain. Kynurenine administered intraperitoneally (150, 450, 900 mg/kg) 2 h before pentylenetetrazol injection dose-dependently increased the time to seizures, the time to death and the survivorship of mice. Kynurenine dose-dependently increased the time to seizures and the time to death in mice with NMDLA-induced seizures. Kynurenine, 900 mg/kg, was equally efficacious to diazepam, 2 mg/kg. Probenecid dose-dependently increased the time to seizures, the time to death and the survivorship of mice with pentylenetetrazol-induced seizures. Probenecid had no significant effects on NMDLA-induced seizures, although the time to death was prolonged in the NMDLA 500 mg/kg group. Probenecid potentiated the effects of kynurenine in these tests. Both probenecid and kynurenine significantly increased kynurenine and kynurenic acid concentrations in mouse cerebral cortex and striatum. These findings suggest that kynurenine (metabolized to kynurenic acid) has anticonvulsant effects, and probenecid potentiates these effects in mice.
Vécsei
L
L
Neurology Service, Massachusetts General Hospital, Boston 02114.
Miller
J
J
MacGarvey
U
U
Beal
M F
MF
D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D003975:Diazepam / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D007736:Kynurenic Acid / Q000378:metabolism*; D007737:Kynurenine / Q000494:pharmacology*; D008297:Male; D051379:Mice; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors / Q000633:toxicity*; D010433:Pentylenetetrazole / Q000037:antagonists & inhibitors / Q000633:toxicity*; D011339:Probenecid / Q000494:pharmacology*; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology* / Q000517:prevention & control
D007737:Kynurenine; D016202:N-Methylaspartate; D007736:Kynurenic Acid; D011339:Probenecid; D003975:Diazepam; D010433:Pentylenetetrazole