title: Quinolinic acid accumulation and functional deficits following experimental spinal cord injury.
abstract: Quinolinic acid (QUIN) is an excitotoxic tryptophan metabolite that is produced by activated macrophages. Accumulations of QUIN are implicated in the aetiology of a broad spectrum of human neurological diseases, particularly inflammatory conditions. To determine whether QUIN is an endogenous neurotoxin requires agents that reduce QUIN synthesis, and animal models where QUIN levels increase in association with neurological disease. Compression injury of the spinal cord of guinea pigs results in secondary neurological deficits, related to inflammation and macrophage activation. We evaluated whether 4-chloro-3-hydroxyanthranilate (4Cl-3HAA), an inhibitor of 3-hydroxyanthranilate-3,4-dioxygenase, reduces QUIN accumulations in this model and influences the progression of neurological deficits. Intraperitoneal injections of 4Cl-3HAA (100 mg/kg every 12 h) attenuated QUIN accumulations in spinal cord following injury, and reduced the severity of delayed functional deficits. Intraperitoneal injections of the macrophage toxin, silica, also reduced QUIN levels and attenuated neurological deficits. A direct subdural infusion of Cl-3HAA into the injured spinal cord (50 microM, 1 microliter/h) promptly exacerbated functional impairments, which suggests that the infusate had direct toxic effects. These studies demonstrate that guinea pigs with spinal cord injury constitute a useful model to study the mechanisms that increase central nervous system (CNS) QUIN levels in conditions of CNS inflammation, and to evaluate the neurochemical and neurological effects of agents designed to reduce the accumulations of QUIN and other potential pathogenic mediators within the CNS. The results are consistent with a contributory role for QUIN in the pathogenesis of secondary functional impairments following spinal cord injury, although the possibility that 4Cl-3HAA had additional effects independent of QUIN cannot be excluded. Further studies are required to determine whether the beneficial effects of 4Cl-3HAA are sustained. While it is unknown whether secondary inflammatory processes contribute significantly to neurological deficits in human spinal cord injury, strategies that reduce the accumulation of QUIN are worthy of consideration and evaluation as a therapeutic target.
authors.affiliation: Division of Neurosurgery, University of North Carolina at Chapel Hill, USA.
authors.forename: A R
authors.initials: AR
authors.lastname: Blight
authors.forename: T I
authors.initials: TI
authors.lastname: Cohen
authors.forename: K
authors.initials: K
authors.lastname: Saito
authors.forename: M P
authors.initials: MP
authors.lastname: Heyes
mesh_terms: D050561:3-Hydroxyanthranilate 3,4-Dioxygenase; D015095:3-Hydroxyanthranilic Acid / Q000031:analogs & derivatives / Q000494:pharmacology / Q000633:toxicity; D000818:Animals; D049308:Dioxygenases; D005073:Evoked Potentials, Somatosensory; D005260:Female; D006168:Guinea Pigs; D008262:Macrophage Activation / Q000187:drug effects; D009187:Myelitis / Q000209:etiology / Q000503:physiopathology; D010105:Oxygenases / Q000037:antagonists & inhibitors; D017378:Quinolinic Acid / Q000378:metabolism*; D012021:Reflex, Abnormal / Q000187:drug effects; D012822:Silicon Dioxide / Q000494:pharmacology; D013117:Spinal Cord Compression / Q000378:metabolism* / Q000473:pathology; D013119:Spinal Cord Injuries / Q000150:complications / Q000378:metabolism* / Q000473:pathology
chemical_list: D015095:3-Hydroxyanthranilic Acid; C026381:4-chloro-3-hydroxyanthranilic acid; D012822:Silicon Dioxide; D010105:Oxygenases; D049308:Dioxygenases; D050561:3-Hydroxyanthranilate 3,4-Dioxygenase; D017378:Quinolinic Acid