Manipulation of brain kynurenines: Glial targets, neuronal effects, and clinical opportunities

被引:444
作者
Schwarcz, R
Pellicciari, R
机构
[1] Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Catonsville, MD 21228 USA
[2] Univ Perugia, Dipartimento Chim & Tecnol Farmaco, I-06100 Perugia, Italy
关键词
D O I
10.1124/jpet.102.034439
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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 alpha7 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.
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页码:1 / 10
页数:10
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