Stys Peter K
University of Ottawa and Ottawa Health Research Institute, 725 Parkdale Avenue, Ottawa, Ont. Canada, K1Y 4K9.
Curr Mol Med. 2004 Mar;4(2):113-30. doi: 10.2174/1566524043479220.
White matter of the brain and spinal cord is susceptible to anoxia, ischemia, trauma and autoimmune attack. Irreversible injury to this tissue can have serious consequences for the overall function of the CNS through disruption of signal transmission. Like neurons, central myelinated axons are critically dependent on a continuous supply of oxygen and glucose. Injury causes failure of the Na-K-ATPase and accumulation of axoplasmic Na through non-inactivating Na channels, which, together with membrane depolarization, promotes reverse Na-Ca exchange and axonal Ca overload. An equally important source of deleterious Ca originates from intracellular stores, released in part by a mechanism similar to "excitation-contraction coupling" in muscle, involving activation of ryanodine receptors by L-type Ca channels. Excitotoxic mechanisms also play an important role: glutamate released by reversal of Na-dependent glutamate transporters activates AMPA/kainate receptors to cause injury to glia and myelin. Excessive accumulation of cytosolic Ca in turn activates various Ca-dependent enzymes such as calpains, phospholipases and others resulting in irreversible injury. Reoxygenation paradoxically accelerates injury in many axons, and promotes cytoskeletal degradation. Blockers of voltage-gated Na channels represent an attractive therapeutic target because of their ability to simultaneously interfere indirectly with several Ca sourcing pathways. Alternatively, or additionally, AMPA/kainate receptor inhibition has also been shown to be neuroprotective in several white matter injury paradigms. In the clinical setting, optimal protection of the CNS as a whole in common disorders such as stroke, traumatic brain and spinal cord injury, will likely require combination therapy aimed at unique steps in gray and white matter regions, or intervention at common points in the injury cascades.
大脑和脊髓的白质易受缺氧、缺血、创伤和自身免疫攻击的影响。该组织的不可逆损伤会通过破坏信号传递对中枢神经系统的整体功能产生严重后果。与神经元一样，中枢有髓轴突严重依赖持续的氧气和葡萄糖供应。损伤会导致钠钾ATP酶功能衰竭，轴浆钠通过非失活钠通道积累，这与膜去极化一起，促进钠钙逆向交换和轴突钙超载。有害钙的另一个同样重要的来源是细胞内储存，部分通过类似于肌肉中“兴奋-收缩偶联”的机制释放，涉及L型钙通道激活兰尼碱受体。兴奋毒性机制也起重要作用：钠依赖性谷氨酸转运体逆转释放的谷氨酸激活AMPA/海人藻酸受体，导致神经胶质和髓鞘损伤。胞质钙的过度积累反过来会激活各种钙依赖性酶，如钙蛋白酶、磷脂酶等，导致不可逆损伤。再灌注反常地加速许多轴突的损伤，并促进细胞骨架降解。电压门控钠通道阻滞剂是一个有吸引力的治疗靶点，因为它们能够同时间接干扰多种钙来源途径。另外，或除此之外，在几种白质损伤模型中，抑制AMPA/海人藻酸受体也已显示具有神经保护作用。在临床环境中，在中风、创伤性脑损伤和脊髓损伤等常见疾病中，对整个中枢神经系统的最佳保护可能需要针对灰质和白质区域独特步骤的联合治疗，或在损伤级联反应的共同点进行干预。
