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Pharmacological Manipulation of Brain Kynurenine Metabolism
Author(s) -
REINHARD JOHN F.
Publication year - 2004
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1196/annals.1332.020
Subject(s) - kynurenine , metabolism , kynurenine pathway , tryptophan metabolism , neuroscience , pharmacology , chemistry , medicine , biology , biochemistry , tryptophan , amino acid
A bstract : The amino acid tryptophan is a precursor for the neurotransmitter serotonin as well as for kynurenic and quinolinic acids. These latter molecules are antagonists and agonists, respectively, of the excitatory amino acid glutamate and arise through the kynurenine pathway of tryptophan metabolism. Significant differences exist in the sites and physiological control of serotonin versus kynurenine. While serotonin is formed within serotonin neurons (in the brain and intestine) and neuroendocrine cells of the intestine, kynurenine is formed by liver cells (as a precursor to nicotinic acid) and in macrophages, activated by inflammatory cytokines. Our studies are based on the hypothesis that inhibition of kynurenine metabolism (at the kynurenine hydroxylase [KH] step) allows the amino acid to be converted to kynurenic acid, a neuroprotective antagonist of excitatory amino acid receptors. Inhibition of KH also prevents formation of the neurotoxic species 3‐hydroxykynurenine and quinolinic acid. To accomplish this end, inhibitors were identified and are described.