Preinjury administration of the calpain inhibitor MDL-28170 attenuates traumatically induced axonal injury
Preinjury administration of the calpain inhibitor MDL-28170 attenuates traumatically induced axonal injury
复制标题
DOI：
10.1089/089771503321532842
复制
发表时间：
2003-03-01
影响因子：
4.2
通讯作者：
Povlishock, JT
中科院分区：
文献类型：
--
作者：
Buki, A;Farkas, O;Povlishock, JT
创伤性脑损伤（TBI）引起弥漫性（创伤性）轴索损伤（TAI），导致发病率和死亡率。受损的轴突表现为进行性改变，逐渐演变为轴突断裂。在严重的TAI中，损伤的张力导致Ca2+局部内流，启动一系列蛋白水解过程，其中半胱氨酸蛋白酶、钙蛋白酶和半胱天冬酶修饰轴突细胞骨架，随着时间的推移造成不可逆的损伤。尽管有几项研究表明全身使用钙蛋白酶抑制剂可以减少缺血性和创伤性挫伤损伤的程度，但迄今为止尚未确定对TAI有直接的有益影响。本研究旨在通过撞击加速大鼠tbi模型来解决这一问题，以进一步证明calpain介导的蛋白水解过程在TAI发病机制中的作用，同时进一步支持calpain抑制剂的应用。损伤前30 min， Wistar大鼠尾静脉单次注射MDL-28170 30 mg/kg。损伤后给予醛类灌注，使大鼠存活120分钟。研究人员对大脑进行免疫组织化学定位，对显示淀粉样蛋白前体蛋白(APP)-或RMO-14免疫反应性（IR）的受损轴突进行定位，两者都被认为是TAL特异性特征的标记，数字数据采集和统计分析表明，损伤前给药MDL-28170显著减少了脑干纤维束中RMO-14-和APP-IR轴突受损的平均数量。这些结果进一步强调了calpain介导的蛋白水解过程在DAI发病机制中的作用，并支持细胞渗透性calpain抑制剂作为TBI合理治疗方法的潜在应用。
Traumatic brain injury (TBI) evokes diffuse (traumatic) axonal injury (TAI), which contributes to morbidity and mortality. Damaged axons display progressive alterations gradually evolving to axonal disconnection. In severe TAI, the tensile forces of injury lead to a focal influx of Ca2+, initiating a series of proteolytic processes wherein the cysteine proteases, calpain and caspase modify the axonal cytoskeleton, causing irreversible damage over time postinjury. Although several studies have demonstrated that the systemic administration of calpain inhibitors reduces the extent of ischemic and traumatic contusional injury a direct beneficial effect on TAI has not been established to date. The current study was initiated to address this issue in an impact acceleration rat-TBI model in order to provide further evidence on the contribution of calpain-mediated proteolytic processes in the pathogenesis of TAI, while further supporting the utility of calpain-inhibitors. A single tail vein bolus injection of 30 mg/kg MDL-28170 was administered to Wistar rats 30 min preinjury. After injury the rats were allowed to survive 120 min when they were perfused with aldehydes. Brains were processed for immunohistochemical localization of damaged axonal profiles displaying either amyloid precursor protein (APP)- or RMO-14-immunoreactivity (IR), both considered markers of specific features of TAL Digital data acquisition and statistical analysis demonstrated that preinjury administration of MDL-28170 significantly reduced the mean number of damaged RMO-14- as well as APP-IR axonal profiles in the brainstem fiber tracts analyzed. These results further underscore the role of calpain-mediated proteolytic processes in the pathogenesis of DAI and support the potential use of cell permeable calpain-inhibitors as a rational therapeutic approach in TBI.