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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.

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.
AuthorsTomoyuki Kita, Paul F Morrison, Melvyn P Heyes, S P Markey
JournalJournal of neurochemistry (J Neurochem) Vol. 82 Issue 2 Pg. 258-68 (Jul 2002) ISSN: 0022-3042 [Print] England
PMID12124427 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Lipopolysaccharides
  • Serum Albumin
  • Tritium
  • Kynurenine
  • Tryptophan
  • Quinolinic Acid
Topics
  • Animals
  • Body Fluid Compartments
  • Brain (metabolism)
  • Corpus Striatum (drug effects, metabolism)
  • Encephalitis (metabolism)
  • Female
  • Gerbillinae
  • Inflammation (chemically induced, metabolism)
  • Injections, Subcutaneous
  • Kidney (metabolism)
  • Kynurenine (administration & dosage, metabolism, pharmacokinetics)
  • Lipopolysaccharides
  • Liver (metabolism)
  • Lung (metabolism)
  • Mass Spectrometry
  • Models, Biological
  • Protein Binding (physiology)
  • Quinolinic Acid (metabolism)
  • Serum Albumin (metabolism)
  • Tissue Distribution
  • Tritium
  • Tryptophan (metabolism)

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