Brain, Vol. 115, No. 5, 1249-1273, 1992
© 1992 Guarantors of Brain
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QUINOLINIC ACID AND KYNURENINE PATHWAY METABOLISM IN INFLAMMATORY AND NON-INFLAMMATORY NEUROLOGICAL DISEASE
1Section on Analytical Biochemistry, Laboratory of Clinical Science NIMH, Bethesda 2Clinical Neuro-endocrinology Branch NIMH, Bethesda 3Child Psychiatry Branch NIMH, Bethesda 4Section on Clinical Pharmacology, Laboratory of Clinical Science NIMH, Bethesda 5Laboratory of Neurochemistry NIMH, Bethesda 6Department of Nuclear Medicine NIH, Bethesda 7Experimental Therapeutics Branch NINDS NIAID, Bethesda 8Laboratory of Clinical Investigation NIAID,Bethesda 9Neurology Service, Veteran's Administration Medical Center Albuquerque 10California Regional Primate Center Davis 11Center for Infectious Diseases, Center for Disease Control Atlanta 12Department of Neurology, The George Washington University washington 13Department of Neurology, Walter Reed Army Medical Center Washington 14Neurology and Research Services and National Neurological Bank Los Angeles, USA 15Department of Pediatrics and Child Health, University of Manitoba Winnipeg, Canada
Correspondence to:
Correspondence to Dr Melvyn P Heyes, Section on Analytical Biochemistry, Laboratory of Clinical Science, Building 10, Room 3D40, National Institute of Mental Health, 9000 Rockville Pike, Bethesda, MD 20892, USA.
Neurological dysfunction, seizures and brain atrophy occur in a broad spectrum of acute and chronic neurological diseases. In certain instances, over-stimulation of N-methyl-D-aspartate receptors has been implicated Quinolinic acid (QUIN) is an endogenous N-methyl-D-aspartate receptor agonist synthesized from L-tryptophan via the kynurenine pathway and thereby has the potential of mediating N-methyl-D-aspartate neuronal damage and dysfunction. Conversely, the related metabolite, kynurenic acid, is an antagonist of N-methyl-D-aspartate receptors and could modulate the neurotoxic effects of QUIN as well as disrupt excitatory amino acid neurotransmission In the present study, markedly increased concentrations of QUIN were found in both lumbar cerebrospinal fluid (CSF) and post-mortem brain tissue of patients with inflammatory diseases (bacterial, viral, fungal and parasitic infections, meningitis, autoimmune diseases and septicaemia) independent of breakdown of the blood-brain barrier. The concentrations of kynurenic acid were also increased, but generally to a lesser degree than the increases in QUIN. In contrast, no increases in CSF QUIN were found in chronic neurodegenerative disorders, depression or myoclonic seizure disorders, while CSF kynurenic acid concentrations were significantly lower in Huntington's disease and Alzheimer's disease. In inflammatory disease patients, proportional increases in CSF L-kynurenine and reduced L-tryptophan accompanied the increases in CSF QUIN and kynurenic acid. These responses are consistent with induction of indoleamine-2,3-dioxygenase, the first enzyme of the kynurenine pathway which converts L-tryptophan to kynurenic acid and QUIN Indeed, increases in both indoleamine-2,3-dioxygenase activity and QUIN concentrations were observed in the cerebral cortex of macaques infected with retrovirus, particularly those with local inflammatory lesions. Correlations between CSF QUIN, kynurenic acid and L-kynurenine with markers of immune stimulation (neopterin, white blood cell counts and lgG levels) indicate a relationship between accelerated kynurenine pathway metabolism and the degree of intracerebral immune stimulation.
We conclude that inflammatory diseases are associated with accumulation of QUIN, kynurenic acid and L-kynurenine within the central nervous system, but that the available data do not support a role for QUIN in the aetiology of Huntington's disease or Alzheimer’s disease In conjunction with our previous reports that CSF QUIN concentrations are correlated to objective measures of neuropsychological deficits in HIV-1-infected patients, we hypothesize that QUIN and kynurenic acid are mediators of neuronal dysfunction and nerve cell death in inflammatory diseases. Therefore, strategies to attenuate the neurological effects of kynurenine pathway metabolites or attenuate the rate of their synthesis offer new approaches to therapy.
Received March 25, 1992. Accepted April 7, 1992.
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