Neuroprotective effects of gelsolin during murine stroke
Neuroprotective effects of gelsolin during murine stroke
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DOI：
10.1172/jci4953
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发表时间：
1999-02-01
影响因子：
15.9
通讯作者：
Moskowitz, MA
中科院分区：
文献类型：
--
作者：
Endres, M;Fink, K;Moskowitz, MA
通过激活的N-甲基-D-天冬氨酸（NMDA）受体和电压依赖性Ca 2+通道（VDCC）增加的Ca 2+内流是脑缺血后细胞损伤的主要决定因素。这些通道的活性由肌动蛋白细胞骨架的动态变化来调节，这可能部分地通过肌动蛋白切割蛋白凝溶胶蛋白的作用来发生。我们发现，凝溶胶蛋白空神经元有增强的细胞死亡和快速，持续升高的Ca 2+水平后，葡萄糖/氧剥夺，以及增强胞质Ca 2+水平在神经末梢后，在体外去极化。此外，与对照组相比，在可逆性大脑中动脉闭塞后的凝溶胶蛋白缺失小鼠中观察到梗死面积的主要增加。此外，用细胞松弛素D（一种解聚肌动蛋白丝的真菌毒素）治疗，将凝溶胶蛋白缺失小鼠和对照小鼠的梗死面积减少到相同的最终体积。因此，凝溶胶蛋白活性的增强或模仿可能在中风期间具有神经保护作用。
Increased Ca2+ influx through activated N-methyl-D-aspartate (NMDA) receptors and voltage-dependent Ca2+ channels (VDCC) is a major determinant of cell injury following brain ischemia. The activity of these channels is modulated by dynamic changes in the actin cytoskeleton, which may occur, in part, through the actions of the actin filament-severing protein gelsolin. We show that gelsolin-null neurons have enhanced cell death and rapid, sustained elevation of Ca2+ levels following glucose/oxygen deprivation, as well as augmented cytosolic Ca2+ levels in nerve terminals following depolarization in vitro. Moreover, major increases in infarct size are seen in gelsolin-null mice after reversible middle cerebral artery occlusion, compared with controls. In addition, treatment with cytochalasin D, a fungal toxin that depolymerizes actin filaments, reduced the infarct size of both gelsolin-null and control mice to the same final volume. Hence, enhancement or mimicry of gelsolin activity may be neuroprotective during stroke.