Elevation of the neurotoxin quinolinic acid occurs following spinal cord trauma

Popovich, Phillip G.; Reinhard, John F.; Flanagan, Ellen; Stokes, Bradford T.

doi:10.1016/0006-8993(94)91560-1

Cited by 60 publications

(33 citation statements)

References 30 publications

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“…One such cascade that has been touted to contribute importantly to the evolution of this secondary damage is the local inflammatory response in the injured spinal cord. Although the neuraxis is considered somehow privileged under an immunological point of view and poorly influenced by inflammatory processes, a large body of recent data suggests the presence of a local inflammatory response and that aspects of this response to injury amplify the secondary damage (Popovich et al, 1994). The cardinal features of inflammation, namely infiltration of inflammatory cells (polymorphonuclear neutrophils, macrophages, and lymphocytes), release Article, publication date, and citation information can be found at…”

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confidence: 99%

Inhibitors of Poly(ADP-Ribose) Polymerase Modulate Signal Transduction Pathways and Secondary Damage in Experimental Spinal Cord Trauma

Genovese

Mazzon

Muià

et al. 2004

J Pharmacol Exp Ther

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Poly(ADP-ribose) polymerase (PARP), a nuclear enzyme activated by strand breaks in DNA, plays an important role in the tissue injury associated with stroke and neurotrauma. The aim of our study was to evaluate the therapeutic efficacy of in vivo inhibition of PARP in an experimental model of spinal cord trauma, which was induced by the application of vascular clips (force of 24g) to the dura via a four-level T5-T8 laminectomy. Spinal cord injury in mice resulted in severe trauma characterized by edema, neutrophil infiltration (measured as an increase in myeloperoxidase activity), and apoptosis (measured by terminal deoxynucleotidyltransferase-mediated UTP end labeling coloration). Infiltration of spinal cord tissue with neutrophils was associated with a marked increase in immunoreactivity for poly(ADP-ribose) (PAR), index of PARP activation, in the spinal cord tissue. These inflammatory events were associated with the activation of nuclear factor-B (NF-B) at 4 h after spinal cord damage. Treatment of the mice with the PARP inhibitors 3-aminobenzamide (3-AB) or 5-aminoisoquinolinone (5-AIQ) significantly reduced the degree of 1) spinal cord inflammation and tissue injury (histological score), 2) PAR formation, 3) neutrophil infiltration, and 4) apoptosis. Treatment with these PARP inhibitors also reduced DNA binding of NF-B and inhibitory B degradation. In a separate set of experiments, we have also demonstrated that PARP inhibitors significantly ameliorated the recovery of limb function (evaluated by motor recovery score). Taken together, our results clearly demonstrate that treatment with PARP inhibitors reduces the development of inflammation and tissue injury events associated with spinal cord trauma.Post-traumatic inflammatory reactions may play an important role in the secondary injury processes after spinal cord injury (SCI) (Bartholdi and Schwab, 1995). The primary traumatic mechanical injury to the spinal cord causes the death of a number of neurons that cannot be recovered or regenerated to date. However, neurons continue to die for hours after SCI, and this represents a potentially avoidable event. This secondary neuronal death is determined by a large number of cellular, molecular, and biochemical cascades. One such cascade that has been touted to contribute importantly to the evolution of this secondary damage is the local inflammatory response in the injured spinal cord. Although the neuraxis is considered somehow privileged under an immunological point of view and poorly influenced by inflammatory processes, a large body of recent data suggests the presence of a local inflammatory response and that aspects of this response to injury amplify the secondary damage (Popovich et al., 1994). The cardinal features of inflammation, namely infiltration of inflammatory cells (polymorphonuclear neutrophils, macrophages, and lymphocytes), release Article, publication date, and citation information can be found at

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confidence: 99%

Inhibitors of Poly(ADP-Ribose) Polymerase Modulate Signal Transduction Pathways and Secondary Damage in Experimental Spinal Cord Trauma

Genovese

Mazzon

Muià

et al. 2004

J Pharmacol Exp Ther

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“…Secondary phase increases the pathology of SCI because of the activation of inflammatory responses [4][5][6]. The expression of NF-kB and other transcription factors like cRel, Rel B, Rel A/p65, p50 and p52 are increased as a result of the activation of inflammatory responses, however, preventing activation of NF-kB can attenuate secondary damage after SCI [7][8][9][10].…”

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confidence: 99%

<i>Dipsacus asperoides</i> (Xue Duan) inhibits spinal cord injury-induced inflammatory responses in rats

Chen¹,

Guo²

2016

Trop. J. Pharm Res

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“…Additional studies of normal animals (Heyes and Markey, 1988), hypoglycemic brain injury , models of hyperammonemia (Robinson et al, 1992), and liver disease (Basile et al, 1995) have used rats. Other investigators have used rats to examine QUIN metabolism in normal animals and evaluate effects of immune stimuli and brain injury (Moroni et al, 1991;Speciale and Schwarcz, 1993;Popovich et al, 1994;Flanagan et al, 1995). In the field of neuroscience, the rat is one of the most frequently used animal species.…”

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Species Heterogeneity Between Gerbils and Rats: Quinolinate Production by Microglia and Astrocytes and Accumulations in Response to Ischemic Brain Injury and Systemic Immune Activation

Heyes

Saito

Chen

et al. 1997

Journal of Neurochemistry

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Quinolinic acid is an excitotoxic kynurenine pathway metabolite, the concentration of which increases in human brain during immune activation. The present study compared quinolinate responses to systemic and brain immune activation in gerbils and rats. Global cerebral ischemia in gerbils, but not rats, increased hippocampus indoleamine-2,3-dioxygenase activity and quinolinate levels 4 days postinjury. In a rat focal ischemia model, small increases in quinolinate concentrations occurred in infarcted regions on days 1, 3, and 7, although concentrations remained below serum values. In gerbils, systemic immune activation by an intraperitoneal injection of endotoxin (1 mg/kg of body weight) increased quinolinate levels in brain, blood, lung, liver, and spleen, with proportional increases in lung indoleamine-2,3-dioxygenase activity at 24 h postinjection. In rats, however, no significant quinolinate content changes occurred, whereas lung indoleamine-2‚3-dioxygenase activity increased slightly. Gerbil, but not rat, brain microglia and peritoneal monocytes produced large quantities of[] tryptophan. Gerbil astrocytes produced relatively small quantities of quinolinate, whereas rat astrocytes produced no detectable amounts. These results demonstrate that the limited capacity of rats to replicate elevations in brain and blood quinolinic acid levels in response to immune activation is attributable to blunted increases in local indoleamine-2,3-dioxygenase activity and a low capacity of microglia, astrocytes, and macrophages to convert L-tryptophan to quinolinate.

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Elevation of the neurotoxin quinolinic acid occurs following spinal cord trauma

Cited by 60 publications

References 30 publications

Inhibitors of Poly(ADP-Ribose) Polymerase Modulate Signal Transduction Pathways and Secondary Damage in Experimental Spinal Cord Trauma

Inhibitors of Poly(ADP-Ribose) Polymerase Modulate Signal Transduction Pathways and Secondary Damage in Experimental Spinal Cord Trauma

<i>Dipsacus asperoides</i> (Xue Duan) inhibits spinal cord injury-induced inflammatory responses in rats

Species Heterogeneity Between Gerbils and Rats: Quinolinate Production by Microglia and Astrocytes and Accumulations in Response to Ischemic Brain Injury and Systemic Immune Activation

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