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Kynurenine Disposition in Blood and Brain of Mice: Effects of Selective Inhibitors of Kynurenine Hydroxylase and of Kynureninase
Author(s) -
Chiarugi Alberto,
Carpenedo Raffaella,
Moroni Flavio
Publication year - 1996
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1996.67020692.x
Subject(s) - kynurenine , quinolinic acid , kynurenic acid , indoleamine 2,3 dioxygenase , kynurenine pathway , biochemistry , metabolite , metabolism , biology , neurotoxin , alanine , chemistry , endocrinology , tryptophan , pharmacology , medicine , amino acid
To study the regulation of the synthesis of quinolinic and kynurenic acids in vivo, we evaluated (a) the metabolism of administered kynurenine by measuring the content of its main metabolites 3‐hydroxykynurenine, anthranilic acid, and 3‐hydroxyanthranilic acid in blood and brain of mice; (b) the effects of ( m ‐nitrobenzoyl)alanine, a selective inhibitor of kynurenine hydroxylase and of ( o ‐methoxybenzoyl)alanine, a selective inhibitor of kynureninase, on this metabolism; and (c) the effects of ( o ‐methoxybenzoyl)alanine on liver kynureninase and 3‐hydroxykynureninase activity. The conclusions drawn from these experiments are (a) the disposition of administered kynurenine preferentially occurs through hydroxylation in brain and through hydrolysis in peripheral tissues; (b) ( m ‐nitrobenzoyl)alanine, the inhibitor of kynurenine hydroxylase, causes the expected changes in brain kynurenine metabolism, such as a decrease of 3‐hydroxykynurenine, and an increase of kynurenic acid; and (c) ( o ‐methoxybenzoyl)alanine, the kynureninase inhibitor, increases brain concentration of the cytotoxic compound 3‐hydroxykynurenine, and unexpectedly does not reduce brain concentration of 3‐hydroxyanthranilic acid, the direct precursor of quinolinic acid. Taken together, the experiments suggest that the systemic administration of a kynurenine hydroxylase inhibitor is a rational approach to increase the brain content of kynurenate and to decrease that of cytotoxic kynurenine metabolites, such as 3‐hydroxykynurenine and quinolinic acid.