Manipulation of Brain Kynurenines: Glial Targets, Neuronal Effects, and Clinical Opportunities
- 1Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, Maryland (R.S.), and 2Dipartimento di Chimica e Tecnologia del Farmaco, University of Perugia, Perugia, Italy (R.P.)
- Robert Schwarcz, Ph.D., Maryland Psychiatric Research Center, P.O. Box 21247, Baltimore, MD 21228. E-mail: rschwarc{at}mprc.umaryland.edu
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
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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.).
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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
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- Received February 6, 2002.
- Accepted May 28, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
