Poly(ADP-ribose) glycohydrolase activity mediates post-traumatic inflammatory reaction after experimental spinal cord trauma
Poly(ADP-ribose) glycohydrolase activity mediates post-traumatic inflammatory reaction after experimental spinal cord trauma
复制标题
DOI：
10.1124/jpet.106.108076
复制
发表时间：
2006-10-01
影响因子：
3.5
通讯作者：
Wang, Zhao-Qi
中科院分区：
文献类型：
--
作者：
Cuzzocrea, Salvatore;Genovese, Tiziana;Wang, Zhao-Qi
本研究的目的是研究聚（ADP-核糖）糖水解酶（PARG）在神经创伤相关的炎症反应和组织损伤的调制中的作用。在野生型（WT）小鼠中通过经由两个节段的T-6至T-7椎板切除术将血管夹（24 g的力）应用于硬脑膜来诱导脊髓创伤。WT小鼠的脊髓损伤导致严重创伤，其特征在于水肿、中性粒细胞浸润和细胞因子产生，随后募集其他炎性细胞、产生一系列炎症介质、组织损伤、细胞凋亡和疾病。在小鼠中PARG基因的遗传破坏或用GPI 16552 [N-双-N，N-二甲基甲酰胺]对PARG的药理学抑制。（3-苯基-丙基）9-氧代-芴-2，7-二酰胺]（40 mg/kg i. p.推注），一种新型的强效PARG抑制剂，显著降低了脊髓炎症和组织损伤的程度（组织学评分）、嗜中性粒细胞浸润、细胞因子产生（肿瘤坏死因子-α和白细胞介素-1 β）和细胞凋亡。在一个单独的实验中，我们已经清楚地表明，PARG抑制显着改善肢体功能的恢复。总之，我们的研究结果表明，PARG活性调节与脊髓创伤相关的炎症反应和组织损伤事件，并参与这些条件下的靶器官损伤。
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 T-6 to T-7 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-alpha and interleukin-1 beta), 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.