Poly(ADP-ribose) glycohydrolase activity mediates post-traumatic inflammatory reaction after experimental spinal cord trauma

Salvatore Cuzzocrea, Tiziana Genovese, Emanuela Mazzon, Concetta Crisafulli, Wookee Min, Rosanna Di Paola, Carmelo Muià, Jia He Li, Emanuela Esposito, Placido Bramanti, Weizheng Xu, Edmond Massuda, Jie Zhang, Zhao Qi Wang

Research output: Contribution to journalArticle

Abstract

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-α and interleukin-1β), 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.

Original languageEnglish
Pages (from-to)127-138
Number of pages12
JournalJournal of Pharmacology and Experimental Therapeutics
Volume319
Issue number1
DOIs
Publication statusPublished - 2006

ASJC Scopus subject areas

  • Pharmacology

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    Cuzzocrea, S., Genovese, T., Mazzon, E., Crisafulli, C., Min, W., Di Paola, R., Muià, C., Li, J. H., Esposito, E., Bramanti, P., Xu, W., Massuda, E., Zhang, J., & Wang, Z. Q. (2006). Poly(ADP-ribose) glycohydrolase activity mediates post-traumatic inflammatory reaction after experimental spinal cord trauma. Journal of Pharmacology and Experimental Therapeutics, 319(1), 127-138. https://doi.org/10.1124/jpet.106.108076