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INFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

Poly(ADP-Ribose) Glycohydrolase Activity Mediates Post-Traumatic Inflammatory Reaction after Experimental Spinal Cord Trauma

Department of Clinical and Experimental Medicine and Pharmacology, Torre Biologica, Policlinico Universitario, Messina, Italy (S.C., T.G., Em.M., C.C., R.D.P., C.M.); Istituto di Ricovero e Cura a Carattere Scientifico Centro Neurolesi "Bonino-Pulejo," Messina, Italy (S.C., T.G., Em.M., P.B.); International Agency for Research on Cancer, Lyon, France (W.M., J.-H.L., Z.-Q.W.); Department of Experimental Pharmacology, University of Naples "Federico II," Napoli, Italy (E.E); Guilford Pharmaceuticals Inc., Baltimore, Maryland (W.X., J.Z.); and Lilium Pharmaceuticals, Cockeysville, Maryland (Ed.M.)

The aim of the present study was to examine the role of poly-(ADP-ribose) glycohydrolase (PARG) on the modulation of the inflammatory response and tissue injury associated with neurotrauma. Spinal cord trauma was induced in wild-type (WT) mice by the application of vascular clips (force of 24 g) to the dura via a two-level T₆ to T₇ laminectomy. Spinal cord injury in WT mice resulted in severe trauma characterized by edema, neutrophil infiltration, and cytokine production followed by recruitment of other inflammatory cells, production of a range of inflammation mediators, tissue damage, apoptosis, and disease. The genetic disruption of the PARG gene in mice or the pharmacological inhibition of PARG with GPI 16552 [N-bis-(3-phenyl-propyl)9-oxo-fluorene-2,7-diamide] (40 mg/kg i.p. bolus), a novel and potent PARG inhibitor, significantly reduced the degree of spinal cord inflammation and tissue injury (histological score), neutrophil infiltration, cytokine production (tumor necrosis factor- and interleukin-1), and apoptosis. In a separate experiment, we have clearly demonstrated that PARG inhibition significantly ameliorated the recovery of limb function. Taken together, our results indicate that PARG activity modulates the inflammatory response and tissue injury events associated with spinal cord trauma and participate in target organ damage under these conditions.

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

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