EUK-207, a superoxide dismutase/catalase mimetic, is neuroprotective against oxygen/glucose deprivation-induced neuronal death in cultured hippocampal slices.
EUK-207, a superoxide dismutase/catalase mimetic, is neuroprotective against oxygen/glucose deprivation-induced neuronal death in cultured hippocampal slices.
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EUK-207 是一种超氧化物歧化酶/过氧化氢酶模拟物，对培养的海马切片中的氧/葡萄糖剥夺诱导的神经元死亡具有神经保护作用。
DOI：
10.1016/j.brainres.2008.10.016
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发表时间：
2009
期刊：
影响因子：
2.9
通讯作者：
Baudry,Michel
中科院分区：
文献类型：
--
作者：
Zhou,Miou;Baudry,Michel
EUK-207是一种合成的超氧化物歧化酶/过氧化氢酶模拟物，已被证明可以逆转小鼠与年龄相关的学习缺陷和大脑氧化应激。在目前的实验中，我们测试了EUK-207对缺氧/葡萄糖剥夺(OGD)诱导的培养海马片细胞死亡的影响，以及几种被认为参与这一过程的机制。培养的海马片在常规培养液中加葡萄糖和氧气后，进行1h的OGD，然后恢复3h或24h。用细胞培养上清液中乳酸脱氢酶(LDH)的释放和切片中的碘化丙啶(PI)摄取量来评价细胞活力。OGD前1小时或2小时应用EUK-207均可显著降低OGD诱导的LDH释放。当在OGD前1小时和恢复24小时期间使用EUK-207时，PI的吸收也被减少。用荧光探针DCF评价OGD诱导的ROS积累。切片中的DCF荧光在OGD处理过程中稳步增加，在恢复到常规介质后迅速消失，在24小时恢复期又缓慢增加。当在OGD后3小时测量时，EUK-207显著降低了升高的ROS水平。OGD还增加了脂质过氧化水平，这种作用在OGD后6小时被EUK-207减弱。OGD后3h，胞浆细胞色素c和核凋亡诱导因子(AIF)含量升高，EUK-207可部分阻断AIF从线粒体到细胞核的移位。总之，EUK-207对OGD诱导的培养海马片细胞死亡具有神经保护作用。由于EUK-207可防止自由基的形成和脂质过氧化，其神经保护作用与消除自由基的产生和脂质过氧化以及减少促凋亡因子的激活有关。我们的数据支持这类分子在预防缺血细胞损伤方面的进一步临床评估。
EUK-207 is a synthetic superoxide dismutase/catalase mimetic that has been shown to reverse age-related learning deficits and brain oxidative stress in mice. In the present experiments, we tested the effects of EUK-207 on oxygen/glucose deprivation (OGD)-induced cell death in cultured hippocampal slices and on several mechanisms that have been postulated to participate in this process. Cultured hippocampal slices were subjected to 1 h OGD followed by 3 or 24 h recovery in regular medium with glucose and oxygen. Lactate dehydrogenase (LDH) release in culture medium and propidium iodide (PI) uptake in slices were used to evaluate cell viability. When EUK-207 was applied either 1 or 2 h before OGD, OGD-induced LDH release was significantly reduced. When EUK-207 was applied 1 h before OGD and during 24 h recovery, PI uptake was also reduced. OGD-induced accumulation of reactive oxygen species (ROS) was evaluated with the fluorescent probe DCF. DCF fluorescence in slices increased steadily during OGD treatment, rapidly disappeared following return to regular medium before slowly increasing again during the 24 h recovery period. When measured 3 h after OGD, increased ROS levels were significantly reduced by EUK-207. OGD also increased lipid peroxidation levels and this effect was also reduced by EUK-207 6 h following OGD. Cytosolic cytochrome c and nuclear apoptosis-inducing factor (AIF) were increased 3 h after OGD, and the translocation of AIF from mitochondria to nucleus was partly blocked by treatment with EUK-207. In conclusion, EUK-207 provides neuroprotection against OGD-induced cell death in cultured hippocampal slices. As EUK-207 prevents free radical formation and lipid peroxidation, the neuroprotection is related to elimination of free radical generation and lipid peroxidation, as well as to decreased activation of pro-apoptotic factors. Our data support the further clinical evaluation of this class of molecules for the prevention of ischemic cell damage.