Okonkwo D O, Povlishock J T
Department of Anatomy, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0709, USA.
J Cereb Blood Flow Metab. 1999 Apr;19(4):443-51. doi: 10.1097/00004647-199904000-00010.
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.
创伤性脑损伤会引发多种轴突病变，这些病变会导致受损轴突最终发生脱连接。在严重的创伤性脑损伤中，轴膜会局部受到扰动，推测这会使钙离子内流，并启动对钙离子敏感的促轴突切断过程。轴膜功能衰竭部位的线粒体可能充当钙离子汇，螯合钙离子以维持细胞质低钙浓度。然而，线粒体内的这种钙离子负荷可能会通过钙离子诱导的通透性转换孔开放导致胶体渗透压肿胀和功能丧失。线粒体的局部功能衰竭反过来又会减少维持膜泵和恢复轴膜通透性改变部位离子平衡所需的高能磷酸盐的产生。作者评估了通透性转换孔抑制剂环孢素A（CsA）预防大鼠撞击加速损伤后轴突节段线粒体肿胀的能力，这些轴突节段的轴膜通透性已发生改变。在电子显微镜水平上，在经CsA预处理的受伤动物的创伤性损伤轴突中，统计学上可见异常线粒体数量较少。此外，这种线粒体保护作用在另一组受伤大鼠中转化为轴突保护作用，这些大鼠的大脑用针对淀粉样前体蛋白的抗体进行反应，淀粉样前体蛋白是受损轴突的已知标志物。CsA预处理显著减少了发生延迟轴突切断的轴突数量，淀粉样前体蛋白免疫反应性轴突密度降低证明了这一点。总的来说，这些研究表明CsA既能保护线粒体，也能保护相关的轴突干，表明这种药物可能对创伤性脑损伤具有治疗作用。
