Evidence for the role of mitogen-activated protein kinase signaling pathways in the development of spinal cord injury
Evidence for the role of mitogen-activated protein kinase signaling pathways in the development of spinal cord injury
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DOI：
10.1124/jpet.107.131060
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发表时间：
2008-04-01
影响因子：
3.5
通讯作者：
Cuzzocrea, Salvatore
中科院分区：
文献类型：
--
作者：
Genovese, Tiziana;Esposito, Emanuela;Cuzzocrea, Salvatore
丝裂原活化蛋白激酶（MAPK）信号通路涉及两种密切相关的MAPK，称为细胞外信号调节激酶（ERK）1和ERK 2。本研究旨在探讨MAPK 3/MAPK 1在实验性脊髓损伤（SCI）继发性损伤中的作用。为此目的，我们使用2-（2-氨基-3-甲氧基苯基）-4H-1-苯并吡喃-4-酮（PD 98059），其是MAPK 3/MAPK 1的抑制剂。通过四节段T5-T8椎板切除术，将血管夹（24 g力）应用于硬脑膜，诱导脊髓创伤。小鼠SCI导致严重创伤，其特征在于水肿、中性粒细胞浸润和炎症介质的产生、组织损伤和细胞凋亡。PD 98059处理（10 mg/kg i. p.）脊髓损伤后1和6 h，1）脊髓炎症和组织损伤程度明显减轻（组织学评分），2）中性粒细胞浸润（髓过氧化物酶活性），3）硝基酪氨酸形成，4）促炎细胞因子表达，5）核因子-κ B活化，6）磷酸化ERK 1/2表达，和6）细胞凋亡（末端脱氧核苷酸转移酶dUTP缺口末端标记染色、Fas配体、Bax和Bcl-2表达）。此外，PD 98059以剂量依赖性方式显著改善肢体功能的恢复（通过运动恢复评分评价）。总之，我们的结果清楚地表明，PD 98059治疗减少了与脊髓创伤相关的炎症和组织损伤的发展。
Mitogen-activated protein kinase (MAPK) signaling pathways involve two closely related MAPKs, known as extracellular signal-regulated kinase (ERK) 1 and ERK2. The aim of the present study was to evaluate the contribution of MAPK3/MAPK1 in the secondary damage in experimental spinal cord injury (SCI) in mice. To this purpose, we used 2-(2-amino-3-methoxyphenyl)-4H- 1-benzopyran-4-one (PD98059), which is an inhibitor of MAPK3/MAPK1. Spinal cord trauma was induced by the application of vascular clips (force of 24 g) to the dura via a four-level T5-T8 laminectomy. SCI in mice resulted in severe trauma characterized by edema, neutrophil infiltration, and production of inflammatory mediators, tissue damage, and apoptosis. PD98059 treatment (10 mg/kg i.p.) at 1 and 6 h after the SCI significantly reduced 1) the degree of spinal cord inflammation and tissue injury (histological score), 2) neutrophil infiltration (myeloperoxidase activity), 3) nitrotyrosine formation, 4) proinflammatory cytokines expression, 5) nuclear factor-kappa B activation, 6) phospho-ERK1/2 expression, and 6) apoptosis (terminal deoxynucleotidyl transferase dUTP nick-end labeling staining, Fas ligand, Bax, and Bcl-2 expression). Moreover, PD98059 significantly ameliorated the recovery of limb function (evaluated by motor recovery score) in a dose-dependent manner. Taken together, our results clearly demonstrate that PD98059 treatment reduces the development of inflammation and tissue injury associated with spinal cord trauma.