Kynurenine Pathway Enzymes in Brain: Responses to Ischemic Brain Injury Versus Systemic Immune Activation

Authors

  • Kuniaki Saito,

    1. Section on Analytical Biochemistry and Section of Clinical Pharmacology, Laboratory of Clinical Science, National Institute of Mental Health, and Stroke Branch, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, U.S.A.
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  • Thaddeus S. Nowak Jr.,

    1. Section on Analytical Biochemistry and Section of Clinical Pharmacology, Laboratory of Clinical Science, National Institute of Mental Health, and Stroke Branch, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, U.S.A.
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  • Kazuhiko Suyama,

    1. Section on Analytical Biochemistry and Section of Clinical Pharmacology, Laboratory of Clinical Science, National Institute of Mental Health, and Stroke Branch, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, U.S.A.
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  • Bonnie J. Quearry,

    1. Section on Analytical Biochemistry and Section of Clinical Pharmacology, Laboratory of Clinical Science, National Institute of Mental Health, and Stroke Branch, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, U.S.A.
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  • Misato Saito,

    1. Section on Analytical Biochemistry and Section of Clinical Pharmacology, Laboratory of Clinical Science, National Institute of Mental Health, and Stroke Branch, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, U.S.A.
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  • Jeffrey S. Crowley,

    1. Section on Analytical Biochemistry and Section of Clinical Pharmacology, Laboratory of Clinical Science, National Institute of Mental Health, and Stroke Branch, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, U.S.A.
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  • Sanford P. Markey,

    1. Section on Analytical Biochemistry and Section of Clinical Pharmacology, Laboratory of Clinical Science, National Institute of Mental Health, and Stroke Branch, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, U.S.A.
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  • Melvyn P. Heyes

    Corresponding author
    1. Section on Analytical Biochemistry and Section of Clinical Pharmacology, Laboratory of Clinical Science, National Institute of Mental Health, and Stroke Branch, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, U.S.A.
    • Address correspondence and reprint requests to Dr. M. P. Heyes at Section on Analytical Biochemistry, Laboratory of Clinical Science, Building 10, Room 3D40, National Institute of Mental Health, Bethesda, MD 20892, U.S.A.

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Abstract

Accumulation of l-kynurenine and quinolinic acid (QUIN) in the brain occurs after either ischemic brain injury or after systemic administration of pokeweed mitogen. Although conversion of l-[13C6]tryptophan to [13C6]-QUIN has not been demonstrated in brain either from normal gerbils or from gerbils given pokeweed mitogen, direct conversion in brain tissue does occur 4 days after transient cerebral ischemia. Increased activities of enzymes distal to indoleamine-2,3-dioxygenase may determine whether l-kynurenine is converted to QUIN. One day after 10 min of cerebral ischemia, the activities of kynureninase and 3-hydroxy-3,4-dioxygenase were increased in the hippocampus, but local QUIN levels and the activities of the indoleamine-2,3-dioxygenase and kynurenine-3-hydroxylase were unchanged. By days 2 and 4 after ischemia, however, the activities of all of these enzymes in the hippocampus as well as QUIN levels were significantly increased. Kynurenine aminotransferase activity in the hippocampus was unchanged on days 1 and 2 after ischemia but was decreased on day 4, at a time when local kynurenic acid levels were unchanged. A putative precursor of QUIN, [13C6]anthranilic acid, was not converted to [13C6]-QUIN in the hippocampus of either normal or 4-day postischemic gerbils. Gerbil macrophages stimulated by endo-toxin in vitro converted l-[13C6]tryptophan to [13Ce]QUIN. Kinetic analysis of kynurenine-3-hydroxylase activity in the cerebral cortex of postischemic gerbils showed that Vmax increased, without changes in Km. Systemic administration of pokeweed mitogen increased indoleamine-2,3-dioxygenase and kynureninase activities in the brain without significant changes in kynurenine-3-hydroxylase or 3-hydroxyanthranilate-3,4-dioxygenase activities. Increases in kynurenine-3-hydroxylase activity, in conjunction with induction of indoleamine-2,3-dioxygenase, kynureninase, and 3-hydroxyanthranilate-3,4-dioxygenase in macro-phage infiltrates at the site of brain injury, may explain the ability of postischemic hippocampus to convert l-[13C6]tryptophan to [13C6]QUIN.

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