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Research ArticlePERSPECTIVES IN PHARMACOLOGY

Manipulation of Brain Kynurenines: Glial Targets, Neuronal Effects, and Clinical Opportunities

Robert Schwarcz and Roberto Pellicciari
Journal of Pharmacology and Experimental Therapeutics October 2002, 303 (1) 1-10; DOI: https://doi.org/10.1124/jpet.102.034439
Robert Schwarcz
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Roberto Pellicciari
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Abstract

Degradation of the essential amino acid tryptophan along the kynurenine pathway (KP) yields several neuroactive intermediates, including the free radical generator 3-hydroxykynurenine, the excitotoxicN-methyl-d-aspartate (NMDA) receptor agonist quinolinic acid, and the NMDA and α7 nicotinic acetylcholine receptor antagonist kynurenic acid. The ambient levels of these compounds are determined by several KP enzymes, which in the brain are preferentially localized in astrocytes and microglial cells. Normal fluctuations in the brain levels of neuroactive KP intermediates might modulate several neurotransmitter systems. Impairment of KP metabolism is functionally significant and occurs in a variety of diseases that affect the brain. Pharmacological agents targeting specific KP enzymes are now available to manipulate the concentration of neuroactive KP intermediates in the brain. These compounds can be used to normalize KP defects, show remarkable efficacy in animal models of central nervous system disorders, and offer novel therapeutic opportunities.

Footnotes

  • Grant support: United States Public Health Service Grants NS 16102 and HD 16596 (to R.S.) and Ministero dell'Università e della Ricerca Scientifica e Tecnologica, Italy-COFIN 2000 (to R.P.).

  • DOI: 10.1124/jpet.102.034439

  • Abbreviations:
    KP
    kynurenine pathway
    l-KYN
    l-kynurenine
    KYNA
    kynurenic acid
    3-HK
    3-hydroxykynurenine
    QUIN
    quinolinic acid
    NMDA
    N-methyl-d-aspartate
    KAT
    kynurenine aminotransferase
    CNS
    central nervous system
    • Received February 6, 2002.
    • Accepted May 28, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 303 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 303, Issue 1
1 Oct 2002
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Research ArticlePERSPECTIVES IN PHARMACOLOGY

Manipulation of Brain Kynurenines: Glial Targets, Neuronal Effects, and Clinical Opportunities

Robert Schwarcz and Roberto Pellicciari
Journal of Pharmacology and Experimental Therapeutics October 1, 2002, 303 (1) 1-10; DOI: https://doi.org/10.1124/jpet.102.034439

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Research ArticlePERSPECTIVES IN PHARMACOLOGY

Manipulation of Brain Kynurenines: Glial Targets, Neuronal Effects, and Clinical Opportunities

Robert Schwarcz and Roberto Pellicciari
Journal of Pharmacology and Experimental Therapeutics October 1, 2002, 303 (1) 1-10; DOI: https://doi.org/10.1124/jpet.102.034439
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  • Article
    • Abstract
    • Neuroactive Tryptophan Metabolites
    • Enzymes of the Kynurenine Pathway
    • Dynamics of Kynurenine Pathway Metabolism in the Periphery and in the Brain
    • Endogenous Kynurenines and Brain Dysfunction
    • Kynurenergic Drugs
    • Outlook: The Road to Kynurenergic Therapies
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