PD98059 protects the brain against mitochondrial-mediated apoptosis and autophagy in a cardiac arrest rat model.
PD98059 protects the brain against mitochondrial-mediated apoptosis and autophagy in a cardiac arrest rat model.
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DOI：
10.1016/j.lfs.2019.116618
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发表时间：
2019-09
期刊：
影响因子：
6.1
通讯作者：
Jun-Hui Zheng;Lu Xie;Nuo Li;Zhao-Yin Fu;X. Tan;R. Tao;T. Qin;Meng-hua Chen
中科院分区：
文献类型：
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作者：
Jun-Hui Zheng;Lu Xie;Nuo Li;Zhao-Yin Fu;X. Tan;R. Tao;T. Qin;Meng-hua Chen
目的线粒体功能障碍被认为是脑缺血再灌注损伤的标志之一。在以前的研究中，我们提供的证据表明，细胞外信号通路（ERK）1/2抑制剂PD 98059通过调节抗氧化剂和抗凋亡活性，改善大鼠心脏骤停/心肺复苏（CA/CPR）的神经功能缺损。由于氧化应激可以激活线粒体依赖的凋亡和自噬，我们进一步探讨了PD 98059对大鼠CA模型中参与凋亡和自噬的线粒体的影响。材料与方法我们在CA/CPR大鼠中处理PD 98059，通过线粒体渗透性转换孔（MPTP）、细胞色素C（CytC）、BCL-2、Bcl-2、Bcl-2和Bcl-2检测复苏后24 h脑组织中线粒体介导的凋亡途径。BAX，caspase-3，以及LC 3，Beclin-1和p62的自噬。PD 98059可降低MPTP开放、CytC释放、caspase 3激活、凋亡指数、LC 3-II、Beclin-1表达，增加P62表达。PD 98059还以剂量依赖性方式抑制复苏后24 h大鼠大脑皮层中的细胞凋亡和自噬活性。PD 98059剂量依赖性抑制ERK信号通路激活后，复苏后24 h大鼠脑皮质磷酸化Drp 1 -616表达下调，TUNEL阳性细胞数和LC 3双标免疫染色阳性细胞数减少。CA/CPR大鼠复苏，这与Drp 1表达下调有关。
AimsMitochondrial dysfunction has been regarded as one of the hallmarks of cerebral ischemia-reperfusion injury. In previous studies, we have provided evidence that the extracellular signaling pathway (ERK) 1/2 inhibitor PD98059 improved the neurological deficits by modulating antioxidant and anti-apoptotic activities in rats subjected to cardiac arrest/cardiopulmonary resuscitation (CA/CPR). Since oxidative stress can activate mitochondria-dependent apoptosis and autophagy, we further explored the effects of PD98059 on mitochondria involved with apoptosis and autophagy in rat CA model.Materials and methodsWe disposed PD98059 in CA/CPR rats, tested the mitochondrial-mediated apoptosis pathway in brain tissues at 24 h post-resuscitation by mitochondrial permeability transition pores (MPTP), cytochromec(CytC), BCL-2, BAX, caspase-3, as well as autophagy by LC3, Beclin-1, and p62. Furthermore, we explored the relationship of dynamin-related protein 1 (Drp1) with apoptosis and autophagy.Key findingsOur study showed that PD98059 decreased the openings of MPTP, CytC release, caspase3 activation, apoptotic indices, LC3-II, Beclin-1and increased P62. PD98059 also inhibited mitochondria-dependent apoptosis and the activity of autophagy in a dose-dependent manner in rat cerebral cortices at 24 h post-resuscitation. The generation of phosphorylated Drp1-616 was down-regulated accompanied by a decrease of TUNEL-positive cells and LC3 in dual immunostaining after PD98059 inhibited activation of ERK signaling pathway in a dose-dependent manner in rat cerebral cortices at 24 h post-resuscitation.SignificancePD98059 protects the brain against mitochondrial-mediated apoptosis and autophagy at 24 h post-resuscitation in rats subjected to CA/CPR, which is linked with the downregulation of Drp1 expression.