4-chloro-3-hydroxyanthranilate reduces local quinolinic acid synthesis, improves functional recovery, and preserves white matter after spinal cord injury.
Inflammatory processes within the central nervous system (CNS) contribute significantly to the pathogenesis of a broad range of neurologic diseases, including spinal cord injury (SCI). One mechanism by which immune activation causes neurologic symptoms and tissue injury is via the production of neurotoxins by activated macrophages and microglia. In the present study, the role of the endogenous tryptophan metabolite and neurotoxin quinolinic acid (QUIN) in secondary pathology following traumatic SCI was investigated. Adult Hartley guinea pigs were injured by lateral compression of the spinal cord at the 12th thoracic segment (T12). QUIN had accumulated at the site of injury on day 12 post-injury in proportion to the severity of functional neurologic deficits (as assessed by the cutaneus trunci muscle reflex and motor function score at 5 h post-injury). Systemic administration of the 3-hydroxyanthranilate-3,4-dioxygenase (3-HAD) inhibitor, 4-chloro-3-hydroxyanthranilate (4Cl-3HAA; approximately 100 mg/kg every 12 h, beginning 5 h after injury) attenuated local QUIN production and reduced QUIN accumulation at the site of injury by approximately 50% at day 12, without enhanced accumulations of the neuroprotective metabolite kynurenic acid (KYNA). The severity of secondary functional deficits was also reduced by 4Cl-3HAA. In toluidine blue-stained spinal cord sections, the area of surviving intact white matter at the injury site was increased by approximately 100% in the 4Cl-3HAA-treated group. Sparing of both axons and myelin contributed to this increase. These results support the conclusion that QUIN accumulations at the site of injury contribute to secondary functional deficits and tissue damage following SCI.
Yates
Jennifer R
JR
Curriculum in Neurobiology and Division of Neurosurgery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. jryates@colby.edu
Heyes
Melvyn P
MP
Blight
Andrew R
AR
D015095:3-Hydroxyanthranilic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000465:Algorithms; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D001812:Blood-Brain Barrier / Q000502:physiology; D005260:Female; D006168:Guinea Pigs; D007736:Kynurenic Acid / Q000378:metabolism; D009186:Myelin Sheath / Q000473:pathology; D010539:Permeability / Q000187:drug effects; D011434:Proprioception / Q000502:physiology; D017378:Quinolinic Acid / Q000378:metabolism*; D012015:Reference Standards; D012023:Reflex, Monosynaptic / Q000502:physiology; D013117:Spinal Cord Compression / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology
D015095:3-Hydroxyanthranilic Acid; C026381:4-chloro-3-hydroxyanthranilic acid; D017378:Quinolinic Acid; D007736:Kynurenic Acid