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Effects of systemic and central nervous system localized inflammation on the contributions of metabolic precursors to the l ‐kynurenine and quinolinic acid pools in brain

2002; Wiley; Volume: 82; Issue: 2 Linguagem: Inglês

10.1046/j.1471-4159.2002.00955.x

1471-4159

Tomoyuki Kita, Paul F. Morrison, Melvyn P. Heyes, Sanford P. Markey,

Gut microbiota and health

Abstract 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, [ 2 H 3 ]‐ 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.