Chen Gang, Shi Ji Xin, Hang Chun Hua, Xie Weiying, Liu Jian, Liu Xiaoming
Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Road, Nanjing 210002, Jiangsu Province, China.
Neurosci Lett. 2007 Oct 2;425(3):177-82. doi: 10.1016/j.neulet.2007.08.022. Epub 2007 Aug 19.
Erythropoietin (EPO) has recently been shown to have a neuroprotective effect in animal models of traumatic brain injury (TBI). However, the precise mechanisms remain unclear. Cerebral inflammation plays an important role in the pathogenesis of secondary brain injury after TBI. We, therefore, tried to analyze how recombinant human erythropoietin (rhEPO) might effect the inflammation-related factors common to TBI: nuclear factor kappa B (NF-kappaB), interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and intercellular adhesion molecule-1 (ICAM-1) in a rat TBI model. Male rats were given 0 or 5000 units/kg injections of rhEPO 1h post-injury and on days 1, 2 and 3 after surgery. Brain samples were extracted at 3 days after trauma. We measured NF-kappaB by electrophoretic mobility shift assay (EMSA); IL-1beta, TNF-alpha and IL-6 by enzyme-linked immunosorbent assay (ELISA); ICAM-1 by immunohistochemistry; brain edema by wet/dry method; blood-brain barrier (BBB) permeability by Evans blue extravasation and cortical apoptosis by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) method. We found that NF-kappaB, pro-inflammatory cytokines and ICAM-1 were increased in all injured animals. In animals given rhEPO post-TBI, NF-kappaB, IL-1beta, TNF-alpha and ICAM-1 were decreased in comparison to vehicle-treated animals. Measures of IL-6 showed no change after rhEPO treatment. Administration of rhEPO reduced brain edema, BBB permeability and apoptotic cells in the injured brain. In conclusion, post-TBI rhEPO administration may attenuate inflammatory response in the injured rat brain, and this may be one mechanism by which rhEPO improves outcome following TBI.
最近研究表明，促红细胞生成素（EPO）在创伤性脑损伤（TBI）动物模型中具有神经保护作用。然而，其确切机制尚不清楚。脑损伤后，脑部炎症在继发性脑损伤的发病机制中起重要作用。因此，我们试图分析重组人促红细胞生成素（rhEPO）如何影响TBI常见的炎症相关因子：核因子κB（NF-κB）、白细胞介素-1β（IL-1β）、肿瘤坏死因子-α（TNF-α）、白细胞介素-6（IL-6）和细胞间黏附分子-1（ICAM-1），采用大鼠TBI模型进行研究。雄性大鼠在受伤后1小时以及术后第1、2和3天，分别注射0或5000单位/千克的rhEPO。在创伤后3天提取脑样本。我们通过电泳迁移率变动分析（EMSA）测量NF-κB；通过酶联免疫吸附测定（ELISA）测量IL-1β、TNF-α和IL-6；通过免疫组织化学测量ICAM-1；通过干湿法测量脑水肿；通过伊文思蓝外渗测量血脑屏障（BBB）通透性；通过末端脱氧核苷酸转移酶介导的dUTP缺口末端标记（TUNEL）法测量皮质细胞凋亡。我们发现，所有受伤动物的NF-κB、促炎细胞因子和ICAM-1均升高。与给予载体处理的动物相比，TBI后给予rhEPO的动物中，NF-κB、IL-1β、TNF-α和ICAM-1降低。rhEPO治疗后，IL-6的测量结果无变化。给予rhEPO可减轻受伤脑内的脑水肿、BBB通透性和凋亡细胞。总之，TBI后给予rhEPO可能会减轻受伤大鼠脑内的炎症反应，这可能是rhEPO改善TBI后预后的一种机制。
