ATTENUATION OF FOCAL CEREBRAL ISCHEMIC-INJURY IN TRANSGENIC MICE OVEREXPRESSING CUZN SUPEROXIDE-DISMUTASE
ATTENUATION OF FOCAL CEREBRAL ISCHEMIC-INJURY IN TRANSGENIC MICE OVEREXPRESSING CUZN SUPEROXIDE-DISMUTASE
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DOI：
10.1073/pnas.88.24.11158
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发表时间：
1991-12-01
影响因子：
11.1
通讯作者：
CHAN, PH
中科院分区：
文献类型：
--
作者：
KINOUCHI, H;EPSTEIN, CJ;CHAN, PH
氧自由基参与缺血再灌注损伤引起的血管源性水肿和梗死的发病机制。在早期的研究中，外源性脂质体包埋的铜锌超氧化物歧化酶（CuZn-SOD）改善局灶性脑缺血大鼠的缺血性脑水肿和梗死。为了直接确定超氧化物歧化酶的作用，在保护超氧化物自由基诱导的损伤，我们测量了梗死面积和水含量24小时后局灶性脑缺血在非转基因小鼠和转基因小鼠携带人SOD 1基因。这些转基因小鼠的脑细胞CuZn-SOD活性比非转基因小鼠高3.1倍。我们还测量了对侧皮质、梗死皮质、周围皮质和纹状体的抗氧化剂水平（还原型谷胱甘肽和还原型抗坏血酸）。与非转基因小鼠相比，转基因小鼠的梗死面积和脑水肿显着减少。还原型谷胱甘肽和还原型抗坏血酸水平下降，在缺血的半球，但在周围的皮质和纹状体的水平显着高于转基因小鼠比非转基因小鼠。这些结果表明，脑内内源性SOD活性的增加降低了缺血性损伤的水平，并支持了超氧自由基在局灶性脑缺血后梗死和水肿的发病机制中起重要作用的概念。
Oxygen-derived free radicals have been implicated in the pathogenesis of vasogenic edema and infarction caused by ischemia and reperfusion injury. In earlier studies, exogenously supplied liposome-entrapped CuZn superoxide dismutase (CuZn-SOD) ameliorated ischemic brain edema and infarction in rats following focal cerebral ischemia. To ascertain directly the role of SOD in the protection against superoxide radical-induced injury, we measured infarct size and water content 24 hr following focal cerebral ischemia in nontransgenic mice and in transgenic mice bearing the human SOD1 gene. These transgenic mice have 3.1-fold higher cellular CuZn-SOD activity in the brain than do their nontransgenic littermates. We also measured antioxidant levels (reduced glutathione and reduced ascorbate) of contralateral cortex, infarct cortex, surrounding cortex, and striatum. Infarct size and brain edema were significantly decreased in transgenic mice compared with nontransgenic mice. Reduced glutathione and reduced ascorbate levels decreased in the ischemic hemisphere, but levels in surrounding cortex and striatum were significantly higher in transgenic mice than in nontransgenic mice. These results indicate that increased endogenous SOD activity in brain reduces the level of ischemic damage and support the concept that superoxide radicals play an important role in the pathogenesis of infarction and edema following focal cerebral ischemia.