Metformin limits apoptosis in primary rat cortical astrocytes subjected to oxygen and glucose deprivation
Metformin limits apoptosis in primary rat cortical astrocytes subjected to oxygen and glucose deprivation
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DOI：
10.5114/fn.2018.80866
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发表时间：
2018-01-01
影响因子：
2
通讯作者：
Liber, Sebastian
中科院分区：
文献类型：
--
作者：
Gabryel, Bozena;Liber, Sebastian
二甲双胍是一种2型抗糖尿病药物和AMP活化蛋白激酶（AMPK）的激活剂，已显示可减少缺血性卒中动物模型中影响星形胶质细胞的梗死面积和病理变化。在这项研究中，我们评估了二甲双胍如何影响细胞活力，细胞凋亡，并确定AMPK的作用，以及JNK p46/ p54和p38激酶，在培养的原代大鼠皮质星形胶质细胞进行12小时的氧和葡萄糖剥夺（OGD）中观察到的现象。二甲双胍提高细胞活力，减少凋亡细胞核的分数，并抑制执行caspase-3的激活。JNK p54和p38活化的减少与Bcl-X-L表达的增加和细胞色素c的线粒体渗漏的减少相关。然而，只有细胞活力和部分凋亡细胞核的分数伴随着AMPK活性的变化而变化，这表明AMPK对二甲双胍介导的作用至关重要，并以不依赖半胱天冬酶的方式调节程序性细胞死亡。JNK和p38抑制剂的实验支持这些激酶在药物相关的线粒体抑制和细胞凋亡外源性途径中的作用。
Metformin, a type 2 anti-diabetic drug and an activator of AMP-activated protein kinase (AMPK), has been shown to reduce infarct size and pathological changes affecting astroglia in animal models of ischemic stroke. In this study, we evaluated how metformin affects cell viability, apoptosis and determined the role of AMPK, as well as JNK p46/ p54 and p38 kinases, in the observed phenomena in the culture of primary rat cortical astrocytes subjected to 12 h of oxygen and glucose deprivation (OGD). Metformin improved cell viability, reduced the fraction of apoptotic nuclei, and inhibited the activation of the executive caspase-3. Decreased activation of JNK p54 and p38 was associated with increased Bcl-X-L expression and decreased mitochondria) leakage of cytochrome c. However, only cell viability and partially the fraction of apoptotic nuclei varied concomitantly with changes in AMPK activity, suggesting that AMPK is critical for metformin-mediated effects and regulates programmed cell death in a caspase-independent manner. Experiments with the inhibitors of JNK and p38 supports the role of these kinases in the drug-related inhibition of mitochondria) and extrinsic pathway of apoptosis.