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

J Neurochem. 2002 Jul;82(2):258-68. doi: 10.1046/j.1471-4159.2002.00955.x.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Body Fluid Compartments
  • Brain / metabolism*
  • Corpus Striatum / drug effects
  • Corpus Striatum / metabolism
  • Encephalitis / metabolism*
  • Female
  • Gerbillinae
  • Inflammation / chemically induced
  • Inflammation / metabolism*
  • Injections, Subcutaneous
  • Kidney / metabolism
  • Kynurenine / administration & dosage
  • Kynurenine / metabolism*
  • Kynurenine / pharmacokinetics
  • Lipopolysaccharides
  • Liver / metabolism
  • Lung / metabolism
  • Mass Spectrometry
  • Models, Biological
  • Protein Binding / physiology
  • Quinolinic Acid / metabolism*
  • Serum Albumin / metabolism
  • Tissue Distribution
  • Tritium
  • Tryptophan / metabolism

Substances

  • Lipopolysaccharides
  • Serum Albumin
  • Tritium
  • Kynurenine
  • Tryptophan
  • Quinolinic Acid