Poly(ADP-Ribose) Synthase Inhibition Reduces Ischemic Injury and Inflammation in Neonatal Rat Brain

Authors

  • S. Ducrocq,

    1. Université René Descartes-INSERM U. 29, Paris, France*Laboratoire de Pharmacologie de la Faculté des Sciences Pharmaceutiques et Biologiques, Paris, France
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  • N. Benjelloun,

    1. Université René Descartes-INSERM U. 29, Paris, France*Laboratoire de Pharmacologie de la Faculté des Sciences Pharmaceutiques et Biologiques, Paris, France
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  • M. Plotkine,

    1. Université René Descartes-INSERM U. 29, Paris, France*Laboratoire de Pharmacologie de la Faculté des Sciences Pharmaceutiques et Biologiques, Paris, France
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  • * Y. Ben-Ari,

    1. Université René Descartes-INSERM U. 29, Paris, France*Laboratoire de Pharmacologie de la Faculté des Sciences Pharmaceutiques et Biologiques, Paris, France
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  • C. Charriaut-Marlangue

    1. Université René Descartes-INSERM U. 29, Paris, France*Laboratoire de Pharmacologie de la Faculté des Sciences Pharmaceutiques et Biologiques, Paris, France
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  • Lippincott Williams & Wilkins, Inc., Philadelphia

  • Abbreviations used: 3-AB, 3-aminobenzamide; CCA, common carotid artery; CCAo, common carotid artery occlusion; MCA, middle cerebral artery; MCAo, middle cerebral artery occlusion; MPO, myeloperoxidase; NO, nitric oxide; NT, nitrotyrosine; PARP, poly(ADP-ribose) polymerase; PARS, poly(ADP-ribose) synthase; PBS, phosphate-buffered saline; PMNL, polymorphonuclear leukocyte.

Address correspondence and reprint requests to Dr. C. Charriaut-Marlangue at her present address: Laboratoire de Pharmacologie de la Faculté des Sciences Pharmaceutiques et Biologiques, 4 Avenue de l’ observatoire, 75006 Paris, France. E-mail: marlangu@pharmacie.univ_paris5.fr

Abstract

Abstract: Poly(ADP-ribose) synthase (PARS), an abundant nuclear protein, has been described as an important candidate for mediation of neurotoxicity by nitric oxide. However, in cerebral ischemia, excessive PARS activation may lead to energy depletion and exacerbation of neuronal damage. We examined the effect of inhibiting PARS on the (a) degree of cerebral injury, (b) process of inflammatory responses, and (c) functional outcomes in a neonatal rat model of focal ischemia. We demonstrate that administration of 3-aminobenzamide, a PARS inhibitor, leads to a significant reduction of infarct volume: 63 ± 2 (untreated) versus 28 ± 4 mm3 (treated). The neuroprotective effects currently observed 48 h postischemia hold up at 7 and 17 days of survival time and attenuate neurological dysfunction. Inhibition of PARS activity, demonstrated by a reduction in poly(ADP-ribose) polymer formation, also reduces neutrophil recruitment and levels of nitrotyrosine, an indicator of peroxynitrite generation. Taken together, our results demonstrate that PARS inhibition reduces ischemic damage and local inflammation associated with reperfusion and may be of interest for the treatment of neonatal stroke.

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