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.
Kita
Tomoyuki
T
Laboratory of Neurotoxicology, National Institute of Mental Health, Bethesda, Maryland 20892, USA.
Morrison
Paul F
PF
Heyes
Melvyn P
MP
Markey
S P
SP
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