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.

• Authors: Tomoyuki Kita, Paul F Morrison, Melvyn P Heyes, S P Markey
• Journal: Journal of neurochemistry (J Neurochem) Vol. 82 Issue 2 Pg. 258-68 (Jul 2002) ISSN: 0022-3042 [Print] England
• PMID: 12124427 (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)