title: Poliovirus induces indoleamine-2,3-dioxygenase and quinolinic acid synthesis in macaque brain.
abstract: Accumulation of the neurotoxin quinolinic acid within the brain occurs in a broad spectrum of patients with inflammatory neurologic disease and may be of neuropathologic significance. The production of quinolinic acid was postulated to reflect local induction of indoleamine 2,3-dioxygenase by cytokines in reactive cells and inflammatory cell infiltrates within the central nervous system. To test this hypothesis, macaques received an intraspinal injection of poliovirus as a model of localized inflammatory neurologic disease. Seventeen days later, spinal cord indoleamine 2,3-dioxygenase activity and quinolinic acid concentrations in spinal cord and cerebrospinal fluid were both increased in proportion to the degree of inflammatory responses and neurologic damage in the spinal cord, as well as the severity of motor paralysis. The absolute concentrations of quinolinic acid achieved in spinal cord and cerebrospinal fluid exceeded levels reported to kill spinal cord neurons in vitro. Smaller increases in indoleamine 2,3-dioxygenase activity and quinolinic acid concentrations also occurred in parietal cortex, a poliovirus target area. In frontal cortex, which is not a target for poliovirus, indoleamine 2,3-dioxygenase was not affected. A monoclonal antibody to human indoleamine 2,3-dioxygenase was used to visualize indoleamine 2,3-dioxygenase predominantly in grey matter of poliovirus-infected spinal cord, in conjunction with local inflammatory lesions. Macrophage/monocytes in vitro synthesized [13C6]quinolinic acid from [13C6]L-tryptophan, particularly when stimulated by interferon-gamma. Spinal cord slices from poliovirus-inoculated macaques in vitro also converted [13C6]L-tryptophan to [13C6]quinolinic acid. We conclude that local synthesis of quinolinic acid from L-tryptophan within the central nervous system follows the induction of indoleamine-2,3-dioxygenase, particularly within macrophage/microglia. In view of this link between immune stimulation and the synthesis of neurotoxic amounts of quinolinic acid, we propose that attenuation of local inflammation, strategies to reduce the synthesis of neuroactive kynurenine pathway metabolites, or drugs that interfere with the neurotoxicity of quinolinic acid offer new approaches to therapy in inflammatory neurologic disease.
authors.affiliation: Section on Analytical Biochemistry, National Institute of Mental Health, Bethesda, Maryland 20892.
authors.forename: M P
authors.initials: MP
authors.lastname: Heyes
authors.forename: K
authors.initials: K
authors.lastname: Saito
authors.forename: D
authors.initials: D
authors.lastname: Jacobowitz
authors.forename: S P
authors.initials: SP
authors.lastname: Markey
authors.forename: O
authors.initials: O
authors.lastname: Takikawa
authors.forename: J H
authors.initials: JH
authors.lastname: Vickers
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D004790:Enzyme Induction; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000494:pharmacology; D008251:Macaca; D011051:Poliomyelitis / Q000378:metabolism*; D017955:Poliovirus; D017378:Quinolinic Acid; D011805:Quinolinic Acids / Q000378:metabolism*; D014364:Tryptophan / Q000378:metabolism; D014366:Tryptophan Oxygenase / Q000096:biosynthesis*
chemical_list: D011805:Quinolinic Acids; D007371:Interferon-gamma; D014364:Tryptophan; D014366:Tryptophan Oxygenase; D017378:Quinolinic Acid