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NEUROPHARMACOLOGY

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

Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Messina, Italy (T.G., E.M., C.M., A.D., S.C.); Centre for Experimental Medicine, Nephrology & Critical Care, William Harvey Research Institute, Queen Mary-University of London, London, United Kingdom (N.S.A.P., C.T.); Department of Pharmacy & Pharmacology, University of Bath, Bath, United Kingdom (M.D.T.); and Centro per lo Studio ed il Trattamento dei Neurolesi Lungodegenti, School of Medicine, University of Messina, Messina, Italy (P.B.)

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.

Address correspondence to: Prof. Salvatore Cuzzocrea, Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Torre Biologica, Policlinico Universitario Via C. Valeria, Gazzi, 98100 Messina Italy. E-mail: salvator{at}unime.it

This article has been cited by other articles:

				S. Cuzzocrea, T. Genovese, E. Mazzon, C. Crisafulli, W. Min, R. Di Paola, C. Muia, J.-H. Li, E. Esposito, P. Bramanti, et al. Poly(ADP-Ribose) Glycohydrolase Activity Mediates Post-Traumatic Inflammatory Reaction after Experimental Spinal Cord Trauma J. Pharmacol. Exp. Ther., October 1, 2006; 319(1): 127 - 138. [Abstract] [Full Text] [PDF]