TY - JOUR
T1 - Poly(ADP-ribose) glycohydrolase activity mediates post-traumatic inflammatory reaction after experimental spinal cord trauma
AU - Cuzzocrea, Salvatore
AU - Genovese, Tiziana
AU - Mazzon, Emanuela
AU - Crisafulli, Concetta
AU - Min, Wookee
AU - Di Paola, Rosanna
AU - Muià, Carmelo
AU - Li, Jia He
AU - Esposito, Emanuela
AU - Bramanti, Placido
AU - Xu, Weizheng
AU - Massuda, Edmond
AU - Zhang, Jie
AU - Wang, Zhao Qi
PY - 2006
Y1 - 2006
N2 - 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.
AB - 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.
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U2 - 10.1124/jpet.106.108076
DO - 10.1124/jpet.106.108076
M3 - Article
C2 - 16825529
AN - SCOPUS:33749040000
SN - 0022-3565
VL - 319
SP - 127
EP - 138
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
IS - 1
ER -