THRESHOLD OF CALCIUM DISTURBANCES AFTER FOCAL CEREBRAL-ISCHEMIA IN RATS - IMPLICATIONS OF THE WINDOW OF THERAPEUTIC OPPORTUNITY
THRESHOLD OF CALCIUM DISTURBANCES AFTER FOCAL CEREBRAL-ISCHEMIA IN RATS - IMPLICATIONS OF THE WINDOW OF THERAPEUTIC OPPORTUNITY
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DOI：
10.1161/01.str.24.8.1212
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发表时间：
1993-08-01
期刊：
影响因子：
8.3
通讯作者：
GROTTA, JC
中科院分区：
文献类型：
--
作者：
DEGRABA, TJ;OSTROW, PT;GROTTA, JC
背景和目的：在人类急性中风试验中，钙通道阻滞剂的不确定结果的一种解释可能是关于钙介导的缺血性神经元损伤的时间过程的信息不完整。本研究探讨了局灶性缺血持续时间与通过钙-钙调素结合测量的细胞内钙增加的功能活性之间的时间关系。通过游离钙调素的免疫组织化学测定，测定60只雄性自发性高血压大鼠在2分钟后和1，2，4，和24小时的永久串联颈总动脉和大脑中动脉闭塞后，以及可逆性大脑中动脉闭塞1和2小时后分别再灌注1和22小时。光镜组织学损伤测定后1小时的闭塞与23小时的再灌注和24小时后occlusion.Results：钙调素染色的核心梗死的显着损失，注意到1小时，并成为最大的缺血4小时后。在缺血1和2小时后再灌注后，未观察到钙调素染色丢失的逆转。光学显微镜下观察到的皮质坏死与最大钙-钙调素结合面积相关。边缘区，以最大结合的中央核心周围的钙调素染色的轻度损失为代表，大小逐渐减小，并在缺血4小时后并入中央核心;它可能代表可逆性缺血的区域。钙-钙调素结合与局灶性缺血持续时间相关，组织学神经元坏死对应于显示钙调蛋白染色显著丧失的皮质区域。由于钙调蛋白染色的丧失代表了缺血后钙介导活性的标志物，因此提示在急性卒中后4小时内存在用钙拮抗剂进行治疗性干预的机会窗口。
Background and Purpose: One explanation for inconclusive results with calcium channel blockers in human acute stroke trials may be incomplete information about the time course of calcium-mediated ischemic neuronal injury. This study explores the temporal relation between duration of focal ischemia and the functional activity of increased intracellular calcium as measured by calcium-calmodulin binding.Methods: Calcium-calmodulin binding, determined by immunohistochemical assay of free calmodulin, was measured in 60 male spontaneously hypertensive rats after 2 minutes and after 1, 2, 4, and 24 hours of permanent tandem common carotid and middle cerebral artery occlusion, and after 1 and 2 hours of reversible middle cerebral artery occlusion followed by 1 and 22 hours of reperfusion, respectively. Light microscopic histological damage was measured after 1 hour of occlusion with 23 hours of reperfusion and after 24 hours of occlusion.Results: Significant loss of calmodulin staining in the core of the infarction was noted by 1 hour and became maximal after 4 hours of ischemia. No reversal of calmodulin staining loss was noted after reperfusion following 1 and 2 hours of ischemia. Cortical necrosis seen by light microscopy correlated well with the area of maximal calcium-calmodulin binding. The border zone area, represented by a mild loss of calmodulin staining surrounding the central core of maximal binding, gradually decreased in size and became incorporated into the central core after 4 hours of ischemia; it may represent an area of reversible ischemia.Conclusions: Calcium-calmodulin binding correlates with duration of focal ischemia, and histological neuronal necrosis corresponds to the cortical areas displaying a significant loss of calmodulin staining. Inasmuch as loss of calmodulin staining represents a marker for calcium-mediated activity after ischemia, it suggests a window of opportunity within 4 hours after acute stroke for therapeutic intervention with calcium antagonists.