Cofilin Inhibition Restores Neuronal Cell Death in Oxygen-Glucose Deprivation Model of Ischemia.
Cofilin Inhibition Restores Neuronal Cell Death in Oxygen-Glucose Deprivation Model of Ischemia.
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DOI：
10.1007/s12035-014-9056-3
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发表时间：
2016-03
影响因子：
5.1
通讯作者：
Shah, Zahoor A.
中科院分区：
文献类型：
--
作者：
Madineni, Anusha;Alhadidi, Qasim;Shah, Zahoor A.
脑缺血是一种与大脑血液供应减少相关的疾病，最终导致神经元死亡。它与一系列不同的反应有关，包括退化和再生机制。在细胞水平上，这种变化主要发生在神经元的细胞骨架上。Cofilin是一种细胞骨架肌动蛋白切断蛋白，已知参与了细胞凋亡的早期阶段。有证据支持它对阿尔茨海默氏症和缺血性肾病等疾病的进展进行干预。在目前的研究中，我们假设Cofilin可能参与了缺血。我们利用PC12细胞和原代培养的小鼠皮质神经元，研究了Cofilin在两种不同的体外缺血模型中的潜在作用：化学诱导的氧化应激和氧-葡萄糖剥夺/再灌注(OGD/R)。表达谱研究表明，在所有的缺血模型中，磷纤维蛋白水平都降低了，这意味着应激诱导的纤维蛋白激活。此外，钙调神经磷酸酶和弹弓蛋白1L(SSH)磷酸酶被发现是cofilin激活的信号媒介。在原代培养的皮质神经元中，COFILIN在OGD后1h被显著激活。为了阐明激活的cofilin在缺血中的作用，我们用siRNA技术敲除了cofilin，并测试了cofilin沉默对神经元存活率的影响。Cofilin siRNA处理的神经元在所有处理组(对照组、OGD组和OGD/R组)的Cofilin水平均显著降低。此外，cofilin siRNA减少了cofilin线粒体的易位和caspase 3的裂解，伴随着神经元存活率的增加。这些结果有力地支持了cofilin在缺血诱导的神经元变性和凋亡中的积极作用。我们相信，靶向这种蛋白介体有可能对缺血性脑损伤和中风进行治疗干预。
Ischemia is a condition associated with decreased blood supply to the brain, eventually leading to death of neurons. It is associated with a diverse cascade of responses involving both degenerative and regenerative mechanisms. At the cellular level, the changes are initiated prominently in the neuronal cytoskeleton. Cofilin, a cytoskeletal actin severing protein, is known to be involved in the early stages of apoptotic cell death. Evidence supports its intervention in the progression of disease states like Alzheimer's and ischemic kidney disease. In the present study, we have hypothesized the possible involvement of cofilin in ischemia. Using PC12 cells and mouse primary cultures of cortical neurons, we investigated the potential role of cofilin in ischemia in two different in vitro ischemic models: chemical induced oxidative stress and oxygen-glucose deprivation/reperfusion (OGD/R). The expression profile studies demonstrated a decrease in phosphocofilin levels in all models of ischemia, implying stress-induced cofilin activation. Furthermore, calcineurin and slingshot 1L (SSH) phosphatases were found to be the signaling mediators of the cofilin activation. In primary cultures of cortical neurons, cofilin was found to be significantly activated after 1 h of OGD. To delineate the role of activated cofilin in ischemia, we knocked down cofilin by siRNA technique and tested the impact of cofilin silencing on neuronal viability. Cofilin siRNA-treated neurons showed a significant reduction of cofilin levels in all treatment groups (control, OGD and OGD/R). Additionally, cofilin siRNA reduced cofilin mitochondrial translocation and caspase 3 cleavage, with a concomitant increase in neuronal viability. These results strongly support the active role of cofilin in ischemia-induced neuronal degeneration and apoptosis. We believe that targeting this protein mediator has a potential for therapeutic intervention in ischemic brain injury and stroke.
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DOI：
10.1152/ajprenal.1999.276.4.f544
发表时间：
1999-04-01
影响因子：
4.2
作者：
Schwartz, N;Hosford, M;Molitoris, BA
通讯作者：
Molitoris, BA
影响因子：
6.1
作者：
Nada, Shadia E.;Shah, Zahoor A.
通讯作者：
Shah, Zahoor A.
影响因子：
9.3
作者：
Hadas S;Spira M;Hanisch UK;Reichert F;Rotshenker S
通讯作者：
Rotshenker S
影响因子：
5.3
作者：
Gitik M;Kleinhaus R;Hadas S;Reichert F;Rotshenker S
通讯作者：
Rotshenker S
影响因子：
6.2
作者：
Lim, Dmitry;Iyer, Anand;Genazzani, Armando A.
通讯作者：
Genazzani, Armando A.