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Metformin limits apoptosis in primary rat cortical astrocytes subjected to oxygen and glucose deprivation.
Folia Neuropathologica ( IF 1.5 ) Pub Date : 2019-02-23 , DOI: 10.5114/fn.2018.80866
Bożena Gabryel , Sebastian Liber

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-XL expression and decreased mitochondrial 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 mitochondrial and extrinsic pathway of apoptosis.

中文翻译:

二甲双胍限制了遭受氧气和葡萄糖剥夺的原代大鼠皮质星形胶质细胞的凋亡。

二甲双胍是一种2型抗糖尿病药物,是AMP激活的蛋白激酶(AMPK)的激活剂,在缺血性中风的动物模型中可减少梗塞面积和影响星形胶质细胞的病理变化。在这项研究中,我们评估了二甲双胍如何影响细胞存活力,细胞凋亡并确定了AMPK以及JNK p46 / p54和p38激酶在原代大鼠皮质星形胶质细胞经受12h氧和葡萄糖剥夺(OGD)。二甲双胍可提高细胞活力,减少凋亡核的比例,并抑制caspase-3的活化。JNK p54和p38的激活减少与Bcl-XL表达增加和细胞色素c的线粒体泄漏减少有关。然而,只有细胞活力和部分凋亡核比例随AMPK活性的变化而变化,这表明AMPK对于二甲双胍介导的作用至关重要,并以与caspase无关的方式调节程序性细胞死亡。用JNK和p38抑制剂进行的实验支持了这些激酶在与药物相关的线粒体抑制和凋亡的外源性途径中的作用。
更新日期:2019-11-01
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