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Drug targets for traumatic brain injury from poly(ADP-ribose)polymerase pathway modulation.
Br J Pharmacol. 2009 Jul; 157(5):695-704.BJ

Abstract

The deleterious pathophysiological cascade induced after traumatic brain injury (TBI) is initiated by an excitotoxic process triggered by excessive glutamate release. Activation of the glutamatergic N-methyl-D-aspartate receptor, by increasing calcium influx, activates nitric oxide (NO) synthases leading to a toxic production of NO. Moreover, after TBI, free radicals are highly produced and participate to a deleterious oxidative stress. Evidence has showed that the major toxic effect of NO comes from its combination with superoxide anion leading to peroxynitrite formation, a highly reactive and oxidant compound. Indeed, peroxynitrite mediates nitrosative stress and is a potent inducer of cell death through its reaction with lipids, proteins and DNA. Particularly DNA damage, caused by both oxidative and nitrosative stresses, results in activation of poly(ADP-ribose) polymerase (PARP), a nuclear enzyme implicated in DNA repair. In response to excessive DNA damage, massive PARP activation leads to energetic depletion and finally to cell death. Since 10 years, accumulating data have showed that inactivation of PARP, either pharmacologically or using PARP null mice, induces neuroprotection in experimental models of TBI. Thus TBI generating NO, oxidative and nitrosative stresses promotes PARP activation contributing in post-traumatic motor, cognitive and histological sequelae. The mechanisms by which PARP inhibitors provide protection might not entirely be related to the preservation of cellular energy stores, but might also include other PARP-mediated mechanisms that needed to be explored in a TBI context. Ten years of experimental research provided rational basis for the development of PARP inhibitors as treatment for TBI.

Authors+Show Affiliations

Equipe de Recherche 'Pharmacologie de la Circulation Cérébrale' (EA 2510), Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris Descartes, Paris, France. valerie.besson@parisdescartes.fr

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

19371326

Citation

Besson, Valerie C.. "Drug Targets for Traumatic Brain Injury From poly(ADP-ribose)polymerase Pathway Modulation." British Journal of Pharmacology, vol. 157, no. 5, 2009, pp. 695-704.
Besson VC. Drug targets for traumatic brain injury from poly(ADP-ribose)polymerase pathway modulation. Br J Pharmacol. 2009;157(5):695-704.
Besson, V. C. (2009). Drug targets for traumatic brain injury from poly(ADP-ribose)polymerase pathway modulation. British Journal of Pharmacology, 157(5), 695-704. https://doi.org/10.1111/j.1476-5381.2009.00229.x
Besson VC. Drug Targets for Traumatic Brain Injury From poly(ADP-ribose)polymerase Pathway Modulation. Br J Pharmacol. 2009;157(5):695-704. PubMed PMID: 19371326.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Drug targets for traumatic brain injury from poly(ADP-ribose)polymerase pathway modulation. A1 - Besson,Valerie C, Y1 - 2009/04/09/ PY - 2009/4/18/entrez PY - 2009/4/18/pubmed PY - 2009/10/14/medline SP - 695 EP - 704 JF - British journal of pharmacology JO - Br J Pharmacol VL - 157 IS - 5 N2 - The deleterious pathophysiological cascade induced after traumatic brain injury (TBI) is initiated by an excitotoxic process triggered by excessive glutamate release. Activation of the glutamatergic N-methyl-D-aspartate receptor, by increasing calcium influx, activates nitric oxide (NO) synthases leading to a toxic production of NO. Moreover, after TBI, free radicals are highly produced and participate to a deleterious oxidative stress. Evidence has showed that the major toxic effect of NO comes from its combination with superoxide anion leading to peroxynitrite formation, a highly reactive and oxidant compound. Indeed, peroxynitrite mediates nitrosative stress and is a potent inducer of cell death through its reaction with lipids, proteins and DNA. Particularly DNA damage, caused by both oxidative and nitrosative stresses, results in activation of poly(ADP-ribose) polymerase (PARP), a nuclear enzyme implicated in DNA repair. In response to excessive DNA damage, massive PARP activation leads to energetic depletion and finally to cell death. Since 10 years, accumulating data have showed that inactivation of PARP, either pharmacologically or using PARP null mice, induces neuroprotection in experimental models of TBI. Thus TBI generating NO, oxidative and nitrosative stresses promotes PARP activation contributing in post-traumatic motor, cognitive and histological sequelae. The mechanisms by which PARP inhibitors provide protection might not entirely be related to the preservation of cellular energy stores, but might also include other PARP-mediated mechanisms that needed to be explored in a TBI context. Ten years of experimental research provided rational basis for the development of PARP inhibitors as treatment for TBI. SN - 1476-5381 UR - https://www.unboundmedicine.com/medline/citation/19371326/Drug_targets_for_traumatic_brain_injury_from_poly_ADP_ribose_polymerase_pathway_modulation_ L2 - https://doi.org/10.1111/j.1476-5381.2009.00229.x DB - PRIME DP - Unbound Medicine ER -