title: Quinolinic acid and kynurenine pathway metabolism in inflammatory and non-inflammatory neurological disease.
abstract: 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 IgG 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.
authors.affiliation: Section on Analytical Biochemistry, NIMH, NIH, Bethesda, MD 20892.
authors.forename: M P
authors.initials: MP
authors.lastname: Heyes
authors.forename: K
authors.initials: K
authors.lastname: Saito
authors.forename: J S
authors.initials: JS
authors.lastname: Crowley
authors.forename: L E
authors.initials: LE
authors.lastname: Davis
authors.forename: M A
authors.initials: MA
authors.lastname: Demitrack
authors.forename: M
authors.initials: M
authors.lastname: Der
authors.forename: L A
authors.initials: LA
authors.lastname: Dilling
authors.forename: J
authors.initials: J
authors.lastname: Elia
authors.forename: M J
authors.initials: MJ
authors.lastname: Kruesi
authors.forename: A
authors.initials: A
authors.lastname: Lackner
mesh_terms: D000368:Aged; D000818:Animals; D001927:Brain Diseases / Q000378:metabolism; D004660:Encephalitis / Q000378:metabolism; D005260:Female; D015658:HIV Infections / Q000134:cerebrospinal fluid / Q000378:metabolism; D006801:Humans; D007736:Kynurenic Acid / Q000134:cerebrospinal fluid / Q000378:metabolism; D007737:Kynurenine / Q000134:cerebrospinal fluid / Q000378:metabolism*; D008251:Macaca; D008297:Male; D008875:Middle Aged; D009422:Nervous System Diseases / Q000134:cerebrospinal fluid / Q000378:metabolism*; D009443:Neuritis / Q000134:cerebrospinal fluid / Q000209:etiology / Q000378:metabolism* / Q000662:veterinary; D017378:Quinolinic Acid / Q000134:cerebrospinal fluid / Q000378:metabolism*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000150:complications
chemical_list: D007737:Kynurenine; D017378:Quinolinic Acid; D007736:Kynurenic Acid