Evidence that kynurenine pathway metabolites mediate hyperbaric oxygen-induced convulsions.
Metabolism of tryptophan (TRP) through the kynurenine (KYN) pathway in brain, liver, and kidney produces intermediates including the neuroactive agonist quinolinic acid (QA) and the antagonists kynurenic acid (KA) and anthranilic acid (AA) for N-methyl D-aspartate (NMDA) receptors in the central nervous system. We hypothesized that elevated concentrations of QA, KA, or AA can moderate the convulsions that are observed during exposure of rats to hyperbaric oxygen (HBO). We found that i.p. administration of TRP or KYN (both of which cross the blood-brain barrier) had no effect on HBO-induced seizures. However, AA (administered i.p.) or gavage administration of the KYN pathway blocking drug Ro 61-8048, both of which enter the brain from the circulatory system, affect the time to first convulsion and/or coma during HBO in a manner consistent with a modulatory role for seizure activity.
Dale
W E
WE
Dalton Cardiovascular Research Center, Research Park Drive, University of Missouri, Columbia, MO 65211, USA. dalew@missouri.edu
Dang
Y
Y
Amiridze
N
N
Brown
O R
OR
D000818:Animals; D003128:Coma / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006931:Hyperbaric Oxygenation / Q000009:adverse effects*; D007737:Kynurenine / Q000378:metabolism* / Q000494:pharmacology; D050601:Kynurenine 3-Monooxygenase; D008297:Male; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control; D013449:Sulfonamides / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors; D014364:Tryptophan / Q000494:pharmacology; D062367:ortho-Aminobenzoates / Q000494:pharmacology
D004791:Enzyme Inhibitors; C110196:Ro 61-8048; D013449:Sulfonamides; D013844:Thiazoles; D062367:ortho-Aminobenzoates; C031385:anthranilic acid; D007737:Kynurenine; D014364:Tryptophan; D006899:Mixed Function Oxygenases; D050601:Kynurenine 3-Monooxygenase