Metformin attenuates cadmium-induced neuronal apoptosis in vitro via blocking ROS-dependent PP5/AMPK-JNK signaling pathway
Metformin attenuates cadmium-induced neuronal apoptosis in vitro via blocking ROS-dependent PP5/AMPK-JNK signaling pathway
复制标题
二甲双胍通过阻断 ROS 依赖性 PP5/AMPK-JNK 信号通路减轻镉诱导的神经细胞凋亡
DOI：
10.1016/j.neuropharm.2020.108065
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发表时间：
2020-09-15
影响因子：
4.7
通讯作者：
Chen, Long
中科院分区：
文献类型：
--
作者：
Chen, Xiaoling;Wu, Wen;Chen, Long
镉（Cd）是一种有毒的环境污染物，可诱导活性氧（ROS）介导的神经元凋亡，导致神经退行性疾病。二甲双胍是一种抗糖尿病药物，由于其对神经退行性疾病的保护作用，最近受到了极大的关注。然而，关于二甲双胍对镉诱导的神经毒性的影响知之甚少。我们发现二甲双胍通过抑制镉对c-Jun N-末端激酶（JNK）的激活，有效地防止了镉诱导的神经元细胞凋亡，这归因于阻断镉对蛋白磷酸酶5（PP 5）和AMP激活蛋白激酶（AMPK）的失活。用SP 600125抑制JNK、敲低c-Jun或过表达PP 5增强二甲双胍对Cd诱导的JNK/c-Jun磷酸化和细胞凋亡的抑制作用。AMPK与AICAR的激活或组成性活性AMPKa的异位表达增强了二甲双胍对镉诱导的JNK/c-Jun磷酸化和细胞凋亡的抑制作用，而显性负性AMPKa的表达减弱了二甲双胍的这些作用。代谢抑制镉诱导的ROS，从而减少细胞死亡。N-乙酰-c-半胱氨酸增强二甲双胍对镉诱导的ROS和细胞凋亡的抑制作用。此外，使用Mito-TEMPO，我们进一步证明二甲双胍通过抑制线粒体ROS的诱导来减弱Cd诱导的细胞死亡。总之，这些结果表明，二甲双胍防止PP 5和AMPK的线粒体ROS失活，从而减弱Cd诱导的JNK激活和神经元细胞凋亡。我们的数据强调，二甲双胍可能是一种有前途的药物，用于预防镉诱导的氧化应激和神经退行性疾病。
Cadmium (Cd), a toxic environment contaminant, induces reactive oxygen species (ROS)-mediated neuronal apoptosis and consequential neurodegenerative disorders. Metformin, an anti-diabetic drug, has recently received a great attention owing to its protection against neurodegenerative diseases. However, little is known regarding the effect of metformin on Cd-induced neurotoxicity. Here we show that metformin effectively prevented Cd-evoked apoptotic cell death in neuronal cells, by suppressing Cd activation of c-Jun N-terminal kinases (JNK), which was attributed to blocking Cd inactivation of protein phosphatase 5 (PP5) and AMP-activated protein kinase (AMPK). Inhibition of JNK with SP600125, knockdown of c-Jun, or overexpression of PP5 potentiated metformin's inhibitory effect on Cd-induced phosphorylation of JNK/c-Jun and apoptosis. Activation of AMPK with AICAR or ectopic expression of constitutively active AMPKa strengthened the inhibitory effects of metformin on Cd-induced phosphorylation of JNK/c-Jun and apoptosis, whereas expression of dominant negative AMPKa weakened these effects of metformin. Metformin repressed Cd-induced ROS, thereby diminishing cell death. N-acetyl-c-cysteine enhanced the inhibitory effects of metformin on Cd-induced ROS and apoptosis. Moreover, using Mito-TEMPO, we further demonstrated that metformin attenuated Cd-induced cell death by suppressing induction of mitochondrial ROS. Taken together, these results indicate that metformin prevents mitochondrial ROS inactivation of PP5 and AMPK, thus attenuating Cd-induced JNK activation and apoptosis in neuronal cells. Our data highlight that metformin may be a promising drug for prevention of Cd-induced oxidative stress and neurodegenerative diseases.