ISSN:
1471-4159
Source:
Blackwell Publishing Journal Backfiles 1879-2005
Topics:
Medicine
Notes:
l-Kynurenine and quinolinic acid are neuroactive l-tryptophan-kynurenine pathway metabolites of potential importance in pathogenesis and treatment of neurologic disease. To identify precursors of these metabolites in brain, [2H3]-l-kynurenine was infused subcutaneously by osmotic pump into three groups of gerbils: controls, CNS-localized immune-activated, and systemically immune-activated. The specific activity of l-kynurenine and quinolinate in blood, brain and systemic tissues at equilibrium was then quantified by mass spectrometry and the results applied to a model of metabolism to differentiate the relative contributions of various metabolic precursors. In control gerbils, 22% of l-kynurenine in brain was derived via local synthesis from l-tryptophan/formylkynurenine versus 78% from l-kynurenine from blood. Quinolinate in brain was derived from several sources, including: local tissue l-tryptophan/formylkynurenine (10%), blood l-kynurenine (35%), blood 3-hydroxykynurenine/3-hydroxyanthranilate (7%), and blood quinolinate (48%). After systemic immune-activation, however, l-kynurenine in brain was derived exclusively from blood, whereas quinolinate in brain was derived from three sources: blood l-kynurenine (52%), blood 3-hydroxykynurenine or 3-hydroxyanthranilate (8%), and blood quinolinate (40%). During CNS-localized immune activation, 〉 98% of both l-kynurenine and quinolinate were derived via local synthesis in brain. Thus, immune activation and its site determine the sources from which l-kynurenine and quinolinate are synthesized in brain. Successful therapeutic modulation of their concentrations must take into account the metabolic and compartment sources.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1046/j.1471-4159.2002.00955.x
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