Effects of metalloporphyrin catalytic antioxidants in experimental brain ischemia
Effects of metalloporphyrin catalytic antioxidants in experimental brain ischemia
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DOI：
10.1016/s0891-5849(02)00979-6
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发表时间：
2002-10-01
影响因子：
7.4
通讯作者：
Warner, DS
中科院分区：
文献类型：
--
作者：
Sheng, HX;Enghild, JJ;Warner, DS
活性氧在大脑对缺血的反应中起着重要作用。采用小鼠大脑中动脉闭塞模型，观察金属卟啉催化抗氧化剂(AEOL 10113和AEOL 10150)对脑缺血再灌注损伤的影响。大鼠大脑中动脉闭塞90min后，侧脑室注射AEOL 10113、AEOL 10150或赋形剂。AEOL 10113和AEOL 10150类似地减少了梗死面积(35%)和神经功能缺陷。AEOL 10113引起的行为副作用是神经保护剂量的两倍，而AEOL 10150需要比神经保护剂量增加15倍才能引起行为变化。AEOL 10150在90min后6h给药，在没有温度影响的情况下，总梗塞面积减少了43%。脑AEOL 10150消除t(1/2)为10h。在小鼠中，MCAO后静脉注射AEOL 10150可减少脑梗塞面积(25%)和神经功能缺失。脑AEOL 10150摄取，在缺血区较大，具有剂量和时间依赖性。AEOL 10150对蛋白质组事件有直接影响，并能改善缺血引起的改变。在原代混合神经元/神经胶质细胞培养中，AEOL 10150以剂量依赖的方式减少乳酸脱氢酶的释放，并选择性地在与体内神经保护浓度一致的浓度下保留乌头酸酶活性。AEOL 10150是一种有效的神经保护化合物，提供了广泛的治疗窗口，对不良行为副作用具有很大的安全性。(C)2002年爱思唯尔科学公司。
Reactive oxygen species play a role in the response of brain to ischemia. The effects of metalloporphyrin catalytic antioxidants (AEOL 10113 and AEOL 10150) were examined after murine middle cerebral artery occlusion (MCAO). Ninety minutes after reperfusion from 90 min MCAO in the rat, AEOL 10113, AEOL 10150, or vehicle were given intracerebroventricularly. AEOL 10113 and AEOL 10150 similarly reduced infarct size (35%) and neurologic deficit. AEOL 10113 caused behavioral side effects at twice the neuroprotective dose while AEOL 10150 required a 15-fold increase from the neuroprotective dose to cause behavioral changes. AEOL 10150, given 6 h after 90 min MCAO, reduced total infarct size by 43% without temperature effects. Brain AEOL 10150 elimination t(1/2) was 10 h. In the mouse, intravenous AEOL 10150 infusion post-MCAO reduced both infarct size (25%) and neurologic deficit. Brain AEOL 10150 uptake, greater in the ischemic hemisphere, was dose- and time-dependent. AEOL 10150 had direct effects on proteomic events and ameliorated changes caused by ischemia. In primary mixed neuronal/glial cultures exposed to 2 h of O-2/glucose deprivation, AEOL 10150 reduced lactate dehydrogenase release dose-dependently and selectively preserved aconitase activity in concentrations consistent with neuroprotection in vivo. AEOL 10150 is an effective neuroprotective compound offering a wide therapeutic window with a large margin of safety against adverse behavioral side effects. (C) 2002 Elsevier Science Inc.