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.
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.
Laboratory of Neurotoxicology, National Institute of Mental Health, Bethesda, Maryland 20892, USA.
Tomoyuki
T
Kita
Paul F
PF
Morrison
Melvyn P
MP
Heyes
S P
SP
Markey
D000818:Animals; D001825:Body Fluid Compartments; D001921:Brain / Q000378:metabolism*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004660:Encephalitis / Q000378:metabolism*; D005260:Female; D005849:Gerbillinae; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism*; D007279:Injections, Subcutaneous; D007668:Kidney / Q000378:metabolism; D007737:Kynurenine / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D008070:Lipopolysaccharides; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D013058:Mass Spectrometry; D008954:Models, Biological; D011485:Protein Binding / Q000502:physiology; D017378:Quinolinic Acid / Q000378:metabolism*; D012709:Serum Albumin / Q000378:metabolism; D014018:Tissue Distribution; D014316:Tritium; D014364:Tryptophan / Q000378:metabolism
D008070:Lipopolysaccharides; D012709:Serum Albumin; D014316:Tritium; D007737:Kynurenine; D014364:Tryptophan; D017378:Quinolinic Acid