An intrathecal bolus of cyclosporin A before injury preserves mitochondrial integrity and attenuates axonal disruption in traumatic brain injury
An intrathecal bolus of cyclosporin A before injury preserves mitochondrial integrity and attenuates axonal disruption in traumatic brain injury
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DOI：
10.1097/00004647-199904000-00010
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发表时间：
1999-04-01
影响因子：
6.3
通讯作者：
Povlishock, JT
中科院分区：
文献类型：
--
作者：
Okonkwo, DO;Povlishock, JT
创伤性脑损伤引起多种轴突病变，导致受损轴突的最终断开。在严重的创伤性脑损伤中，轴膜被局部扰动，可能允许Ca2+内流和启动Ca2+敏感的proaxotomy过程。轴膜衰竭灶中的线粒体可能作为钙汇，螯合钙以保持低的细胞质钙浓度。然而，线粒体内的这种Ca2+负荷可能通过Ca2+诱导的渗透性转换孔的开放引起胶体渗透性肿胀和功能丧失。线粒体的局部失效，反过来，可以减少维持膜泵所必需的高能磷酸盐的产生，并恢复轴膜通透性变化灶中的离子平衡。作者评价了渗透性转换孔抑制剂环孢菌素A（CsA）防止损伤轴突节段中线粒体肿胀的能力，表明大鼠冲击加速度损伤后轴膜渗透性改变。在电子显微镜水平上，统计学上较少的异常线粒体中看到创伤性损伤的轴突从CsA预处理损伤的动物。此外，在第二组受伤的大鼠中，这种线粒体保护转化为轴突保护，这些大鼠的大脑与抗淀粉样前体蛋白的抗体反应，淀粉样前体蛋白是受损轴突的已知标志物。CsA预处理显著减少了延迟性轴突切断术的轴突数量，淀粉样前体蛋白免疫反应性轴突的密度降低就是证明。总的来说，这些研究表明，CsA保护线粒体和相关的轴突轴，这表明这种药物可能是创伤性脑损伤的治疗用途。
Traumatic brain injury evokes multiple axonal pathologies that contribute to the ultimate disconnection of injured axons. In severe traumatic brain injury, the axolemma is perturbed focally, presumably allowing for the influx of Ca2+ and initiation of Ca2+-sensitive, proaxotomy processes. Mitochondria in foci of axolemmal failure may act as Ca2+ sinks that sequester Ca2+ to preserve low cytoplasmic calcium concentrations. This Ca2+ load within mitochondria, however, may cause colloid osmotic swelling and loss of function by a Ca2+-induced opening of the permeability transition pore. Local failure of mitochondria, in turn, can decrease production of high-energy phosphates necessary to maintain membrane pumps and restore ionic balance in foci of axolemmal permeability change. The authors evaluated the ability of the permeability transition pore inhibitor cyclosporin A (CsA) to prevent mitochondrial swelling in injured axonal segments demonstrating altered axolemmal permeability after impact acceleration injury in rat. At the electron microscopic level, statistically fewer abnormal mitochondria were seen in traumatically injured axons from CsA-pretreated injured animals. Further, this mitochondrial protection translated into axonal protection in a second group of injured rats, whose brains were reacted with antibodies against amyloid precursor protein, a known marker of injured axons. Pretreatment with CsA significantly reduced the number of axons undergoing delayed axotomy, as evidenced by a decrease in the density of amyloid precursor protein-immunoreactive axons. Collectively, these studies demonstrate that CsA protects both mitochondria and the related axonal shaft, suggesting that this agent may be of therapeutic use in traumatic brain injury.