Quinolinic acid accumulation and functional deficits following experimental spinal cord injury

Andrew R. Blight, Timothy I. Cohen, Kuniaki Saito, Melvyn P. Heyes

Research output: Contribution to journalArticle

93 Citations (Scopus)

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 μM, I μl/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.

Original languageEnglish
Pages (from-to)735-752
Number of pages18
JournalBrain
Volume118
Issue number3
DOIs
Publication statusPublished - 01-06-1995

Fingerprint

Quinolinic Acid
Spinal Cord Injuries
Central Nervous System
Intraperitoneal Injections
3-Hydroxyanthranilate 3,4-Dioxygenase
Guinea Pigs
Macrophages
Inflammation
Spinal Cord Compression
Macrophage Activation
Poisons
Neurotoxins
Tryptophan
Silicon Dioxide

All Science Journal Classification (ASJC) codes

  • Clinical Neurology

Cite this

Blight, Andrew R. ; Cohen, Timothy I. ; Saito, Kuniaki ; Heyes, Melvyn P. / Quinolinic acid accumulation and functional deficits following experimental spinal cord injury. In: Brain. 1995 ; Vol. 118, No. 3. pp. 735-752.
@article{11beeb44f50745d2878c93b860c90bd9,
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 μM, I μl/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.",
author = "Blight, {Andrew R.} and Cohen, {Timothy I.} and Kuniaki Saito and Heyes, {Melvyn P.}",
year = "1995",
month = "6",
day = "1",
doi = "10.1093/brain/118.3.735",
language = "English",
volume = "118",
pages = "735--752",
journal = "Brain",
issn = "0006-8950",
publisher = "Oxford University Press",
number = "3",

}

Quinolinic acid accumulation and functional deficits following experimental spinal cord injury. / Blight, Andrew R.; Cohen, Timothy I.; Saito, Kuniaki; Heyes, Melvyn P.

In: Brain, Vol. 118, No. 3, 01.06.1995, p. 735-752.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Quinolinic acid accumulation and functional deficits following experimental spinal cord injury

AU - Blight, Andrew R.

AU - Cohen, Timothy I.

AU - Saito, Kuniaki

AU - Heyes, Melvyn P.

PY - 1995/6/1

Y1 - 1995/6/1

N2 - 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 μM, I μl/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.

AB - 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 μM, I μl/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.

UR - http://www.scopus.com/inward/record.url?scp=0029061019&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0029061019&partnerID=8YFLogxK

U2 - 10.1093/brain/118.3.735

DO - 10.1093/brain/118.3.735

M3 - Article

VL - 118

SP - 735

EP - 752

JO - Brain

JF - Brain

SN - 0006-8950

IS - 3

ER -