Rapamycin Confers Neuroprotection against Colistin-Induced Oxidative Stress, Mitochondria Dysfunction, and Apoptosis through the Activation of Autophagy and mTOR/Akt/CREB Signaling Pathways
Rapamycin Confers Neuroprotection against Colistin-Induced Oxidative Stress, Mitochondria Dysfunction, and Apoptosis through the Activation of Autophagy and mTOR/Akt/CREB Signaling Pathways
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DOI：
10.1021/acschemneuro.7b00323
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发表时间：
2018-04-01
影响因子：
5
通讯作者：
Xiao, Xilong
中科院分区：
文献类型：
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作者：
Dai, Chongshan;Ciccotosto, Giuseppe D.;Xiao, Xilong
我们前期的研究表明，粘菌素诱导的神经毒性涉及细胞凋亡和氧化损伤。本研究证明了雷帕霉素在体外和体内对粘菌素诱导的神经毒性具有神经保护作用。在小鼠模型中，粘菌素给药（18 mg/kg/d; 14天）在大脑皮层中产生了显著的神经元线粒体损伤，并增加了半胱天冬酶-9和-3的活化。雷帕霉素联合治疗（2.5 mg/kg/d）有效地降低了这种神经毒性作用。在体外小鼠神经母细胞瘤-2a（N2 a）细胞培养模型中，雷帕霉素预处理（500 nM）将粘菌素（200 μ M）诱导的细胞死亡从相似的50%降低至72%。此外，雷帕霉素在N2 a细胞中显示出显著的神经保护作用，通过减少细胞内活性氧（ROS）的产生，上调抗ROS酶超氧化物歧化酶和过氧化氢酶的活性，并将谷胱甘肽（GSH）水平恢复至正常水平。此外，雷帕霉素预处理通过上调自噬和激活Akt/CREB、NGF和Nrf 2通路，同时抑制p53信号传导，保护免受粘菌素诱导的线粒体功能障碍、半胱天冬酶激活和随后的细胞凋亡。总之，这是第一项证明雷帕霉素通过激活自噬、抑制氧化应激、线粒体功能障碍和细胞凋亡来防止粘菌素诱导的神经毒性的研究。我们的数据强调，调节自噬以拯救神经元免于凋亡可能成为一种新的靶向治疗，以减轻与粘菌素治疗相关的不良神经毒性作用。
Our previous studies showed that colistininduced neurotoxicity involves apoptosis and oxidative damage. The present study demonstrates a neuroprotective effect of rapamycin against colistin-induced neurotoxicity in vitro and in vivo. In a mouse model, colistin treatment (18 mg/kg/d; 14 days) produced marked neuronal mitochondria damage in the cerebral cortex and increased activation of caspase-9 and -3. Rapamycin cotreatment (2.5 mg/kg/d) effectively reduced this neurotoxic effect. In an in vitro mouse neuroblastoma-2a (N2a) cell culture model, rapamycin pretreatment (500 nM) reduced colistin (200 mu M) induced cell death from similar to 50% to 72%. Moreover, rapamycin showed a marked neuroprotective effect in the N2a cells by decreasing intracellular reactive oxygen species (ROS) production and by up-regulating the activities of the anti-ROS enzymes superoxide dismutase and catalase and recovering glutathione (GSH) levels to normal. Moreover, rapamycin pretreatment protected against colistin-induced mitochondrial dysfunction, caspase activation, and subsequent apoptosis by up-regulating autophagy and activating the Akt/CREB, NGF, and Nrf2 pathways, while inhibiting p53 signaling. Taken together, this is the first study to demonstrate that rapamycin protects against colistin-induced neurotoxicity by activating autophagy, inhibiting oxidative stress, mitochondria dysfunction, and apoptosis. Our data highlight that regulating autophagy to rescue neurons from apoptosis may become a new targeted therapy to relieve the adverse neurotoxic effects associated with colistin therapy.