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.
Footnotes
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This work was supported by a grant from Ministero dell'Università e della Ricerca Scientifica e Tecnologica.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.108076.
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ABBREVIATIONS: SCI, spinal cord injury; ROS, reactive oxygen species; PARP, poly(ADP-ribose) polymerase; PARG, poly(ADP-ribose) glycohydrolase; GPI 16552, N-bis-(3-phenyl-propyl)9-oxo-fluorene-2,7-diamide; KO, knockout; WT, wild type; MPO, myeloperoxidase; PI, propidium iodide; FITC, fluorescein isothiocyanate; PBS, phosphate-buffered saline; TNF, tumor necrosis factor; IL, interleukin; TUNEL, terminal deoxynucleotidyl transferase dUTP nick-end labeling; i.p. intraperitoneally.
- Received May 18, 2006.
- Accepted July 5, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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