Department of Emergency and Intensive Care Unit, The Second Affiliated Hospital of Soochow University, Suzhou, China.
Department of Neurology, The Second Affiliated Hospital, Institute of Neuroscience, Soochow University, 1055 Sanxiang Road, Suzhou, 215004, China.
Mol Cell Biochem. 2019 Nov;461(1-2):81-89. doi: 10.1007/s11010-019-03592-x. Epub 2019 Jul 24.
In pathogenesis of Parkinson's disease (PD), mitochondrial dysfunction causes substantial reactive oxygen species (ROS) production and oxidative stress, leading to dopaminergic (DA) neuronal cell death. Mitochondrial toxins, including MPP (1-methyl-4-phenylpyridinium ion) and rotenone, induce oxidative injury in cultured DA neuronal cells. The current study tested the potential effect of SC79, a first-in-class small-molecule Akt activator, against the process. In SH-SY5Y cells and primary murine DA neurons, SC79 significantly attenuated MPP- and rotenone-induced viability reduction, cell death, and apoptosis. SC79 activated Akt signaling in DA neuronal cells. Akt inhibition (by LY294002 and MK-2206) or CRISPR-Cas9-mediated Akt1 knockout completely abolished SC79-induced DA neuroprotection against MPP. Further studies demonstrated that SC79 attenuated MPP- and rotenone-induced ROS production, mitochondrial depolarization, and lipid peroxidation in SH-SY5Y cells and primary DA neurons. Moreover, upregulation of Nrf2-dependent genes (HO1 and NQO1) and Nrf2 protein stabilization were detected in SC79-treated SH-SY5Y cells and primary DA neurons. Together we show that SC79 protects DA neuronal cells from mitochondrial toxins possibly via activation of Akt-Nrf2 signaling.
在帕金森病（PD）的发病机制中，线粒体功能障碍导致大量活性氧（ROS）的产生和氧化应激，从而导致多巴胺能（DA）神经元细胞死亡。线粒体毒素，包括 MPP（1-甲基-4-苯基吡啶离子）和鱼藤酮，在培养的 DA 神经元细胞中诱导氧化损伤。本研究测试了 Akt 激活剂 SC79 对该过程的潜在作用。在 SH-SY5Y 细胞和原代小鼠 DA 神经元中，SC79 显著减弱了 MPP 和鱼藤酮诱导的活力降低、细胞死亡和细胞凋亡。SC79 激活了 DA 神经元细胞中的 Akt 信号通路。Akt 抑制（通过 LY294002 和 MK-2206）或 CRISPR-Cas9 介导的 Akt1 敲除完全消除了 SC79 诱导的对 MPP 的 DA 神经保护作用。进一步的研究表明，SC79 减弱了 SH-SY5Y 细胞和原代 DA 神经元中 MPP 和鱼藤酮诱导的 ROS 产生、线粒体去极化和脂质过氧化。此外，在 SC79 处理的 SH-SY5Y 细胞和原代 DA 神经元中检测到 Nrf2 依赖性基因（HO1 和 NQO1）和 Nrf2 蛋白稳定的上调。总之，我们表明 SC79 可能通过激活 Akt-Nrf2 信号通路来保护 DA 神经元细胞免受线粒体毒素的侵害。
