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Vol. 303, Issue 1, 1-10, October 2002

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

Robert Schwarcz and Roberto Pellicciari

Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, Maryland (R.S.), and Dipartimento di Chimica e Tecnologia del Farmaco, University of Perugia, Perugia, Italy (R.P.)

Degradation of the essential amino acid tryptophan along the kynurenine pathway (KP) yields several neuroactive intermediates, including the free radical generator 3-hydroxykynurenine, the excitotoxic N-methyl-D-aspartate (NMDA) receptor agonist quinolinic acid, and the NMDA and alpha 7 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.

0022-3565/02/3031-0001$07.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics


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