Barut Seref, Unlü Yusuf Atilla, Karaoğlan Alper, Tunçdemir Matem, Dağistanli Fatma Kaya, Oztürk Melek, Colak Ahmet
Neurosurgery Clinic, Taksim Education and Research Hospital, Istanbul, Turkey, 34144.
Surg Neurol. 2005 Sep;64(3):213-20; discussion 220. doi: 10.1016/j.surneu.2005.03.042.
Apoptosis is one of the most important forms of cell death seen in a variety of physiological and pathological conditions, including traumatic injuries. This type of cell death occurs via mediators known as caspases. Previous studies have investigated the roles that apoptosis and different caspases play in the pathogenesis of secondary damage after spinal cord injury (SCI). The aim of this research was to assess the neuroprotective effect of z-DEVD.fmk, a caspase-3 inhibitor, in a rat model of SCI.
Forty-five Wistar albino rats were studied in 3 groups of 15 animals: sham-operated control animals (group 1); trauma-only control animals (group 2); and rats subjected to trauma + z-DEVD.fmk treatment (group 3). Spinal cord injury was produced at the thoracic level using the weight-drop technique. Responses to injury and the efficacy of z-DEVD.fmk were assessed by light microscopy and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling staining in cord tissues collected at 4 and 24 hours posttrauma. Five rats from each group were used to assess functional recovery at 7 days after SCI. The functional evaluations were done using the inclined-plane technique and a modified Tarlov motor grading scale.
At 4 hours postinjury, the mean apoptotic index in groups 1, 2, and 3 was 0, 33.01+/-6.62, and 16.40+/-4.91, respectively. The group 3 count was significantly lower than the group 2 count (P<.01). At 24 hours postinjury, light microscopic examination of group 2 tissues showed widespread hemorrhage, necrosis, polymorphonuclear leukocyte infiltration, and vascular thrombi. The group 3 tissues showed similar features. The prominent findings in group 2 were hemorrhage and necrosis, whereas the prominent findings in group 3 were focal hemorrhage and leukocyte infiltration. The mean inclined-plane angles in groups 1, 2, and 3 were 64.5 degrees+/-1.0 degrees, 41.5 degrees+/-1.3 degrees, and 47 degrees+/-2.0 degrees, respectively. Motor scale results in all groups showed a similar trend.
Local application of z-DEVD.fmk after SCI in rats reduces secondary tissue injury and helps preserve motor function. These effects can be explained by inhibition of apoptotic death in all cell types in the spinal cord.
细胞凋亡是在包括创伤性损伤在内的多种生理和病理条件下所见到的最重要的细胞死亡形式之一。这种类型的细胞死亡通过被称为半胱天冬酶的介质发生。先前的研究已经调查了细胞凋亡和不同的半胱天冬酶在脊髓损伤（SCI）后继发性损伤发病机制中所起的作用。本研究的目的是评估半胱天冬酶-3抑制剂z-DEVD.fmk在大鼠SCI模型中的神经保护作用。
45只Wistar白化大鼠被分为3组，每组15只动物：假手术对照动物（第1组）；仅创伤对照动物（第2组）；以及接受创伤+z-DEVD.fmk治疗的大鼠（第3组）。使用重物坠落技术在胸段造成脊髓损伤。通过光学显微镜以及在创伤后4小时和24小时收集的脊髓组织中的末端脱氧核苷酸转移酶介导的脱氧尿苷三磷酸缺口末端标记染色来评估对损伤的反应和z-DEVD.fmk的疗效。每组5只大鼠用于评估SCI后7天的功能恢复情况。功能评估使用斜面技术和改良的塔尔洛夫运动评分量表进行。
损伤后4小时，第1组、第2组和第3组的平均凋亡指数分别为0、33.01±6.62和16.40±4.91。第3组的计数显著低于第2组（P<0.01）。损伤后24小时，第2组组织的光学显微镜检查显示广泛出血、坏死、多形核白细胞浸润和血管血栓形成。第3组组织表现出类似特征。第2组的突出发现是出血和坏死，而第3组的突出发现是局灶性出血和白细胞浸润。第1组、第2组和第3组的平均斜面角度分别为64.5度±1.0度、41.5度±1.3度和47度±2.0度。所有组的运动评分结果显示出类似趋势。
大鼠SCI后局部应用z-DEVD.fmk可减少继发性组织损伤并有助于保留运动功能。这些作用可以通过抑制脊髓中所有细胞类型的凋亡性死亡来解释。
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