Siesjö B K, Zhao Q, Pahlmark K, Siesjö P, Katsura K, Folbergrová J
Laboratory for Experimental Brain Research, University of Lund, University Hospital, Sweden.
Ann Thorac Surg. 1995 May;59(5):1316-20. doi: 10.1016/0003-4975(95)00077-x.
Calcium is considered a mediator of ischemic brain damage whether this is due to global or forebrain ischemia or to focal ischemia. Supporting evidence is the translocation of extracellular calcium into cells during ischemia, the precipitous rise in the free cytosolic calcium concentration, and the role of calcium in activating lipases, proteases, kinases, phosphatases, and endonucleases in potentially harmful metabolic cascades. In vitro and in vivo experiments suggest that the main route of entry is through channels gated by glutamate receptors. These experiments led to the excitotoxic hypothesis of cell death. The in vitro experiments further support the role of calcium as a mediator of cell death. Both cell calcium overload and acidosis enhance the production of partially reduced oxygen species, thus predisposing to free radical-related damage. In transient global or forebrain ischemia, free radicals formed during reperfusion may contribute to a perturbed membrane function, leading to a sustained alteration of cell calcium metabolism with ultimate mitochondrial calcium overload. In focal ischemia (stroke), free radicals may be important mediators of the infarction process. Infarction can be regarded as a form of secondary damage, which is probably caused by microvascular dysfunction. Very likely, such dysfunction is triggered by upregulation of adhesion molecules such as ICAM-1, microvascular "plugging," and an inflammatory response at the blood-endothelial cell interface. The involvement of free radicals in this type of secondary damage is supported by results showing that nitrones that act as free radical spin-traps ameliorate focal ischemic damage with a therapeutic window of many hours.
钙被认为是缺血性脑损伤的介质，无论这种损伤是由于全脑或前脑缺血，还是局灶性缺血所致。支持这一观点的证据包括：缺血期间细胞外钙向细胞内的转运、胞质游离钙浓度的急剧升高，以及钙在激活脂肪酶、蛋白酶、激酶、磷酸酶和核酸内切酶从而引发潜在有害代谢级联反应中的作用。体外和体内实验表明，钙进入细胞的主要途径是通过由谷氨酸受体门控的通道。这些实验导致了细胞死亡的兴奋性毒性假说。体外实验进一步支持了钙作为细胞死亡介质的作用。细胞钙超载和酸中毒均会增强部分还原氧物种的产生，从而易引发自由基相关损伤。在短暂性全脑或前脑缺血中，再灌注期间形成的自由基可能导致膜功能紊乱，进而导致细胞钙代谢持续改变，最终引起线粒体钙超载。在局灶性缺血（中风）中，自由基可能是梗死过程的重要介质。梗死可被视为一种继发性损伤形式，可能由微血管功能障碍引起。很可能，这种功能障碍是由细胞间黏附分子-1（ICAM-1）等黏附分子上调、微血管“阻塞”以及血-内皮细胞界面的炎症反应触发的。自由基参与这种继发性损伤的观点得到了以下结果的支持：作为自由基自旋捕获剂的硝酮可在数小时的治疗窗内减轻局灶性缺血损伤。
