Chen Xiao, Xi Zhiyu, Liang Huaibin, Sun Yuhao, Zhong Zhihong, Wang Baofeng, Bian Liuguan, Sun Qingfang
Department of Neurosurgery, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Department of Neurology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Front Neurosci. 2019 Jul 25;13:760. doi: 10.3389/fnins.2019.00760. eCollection 2019.
Secondary injuries mediated by oxidative stress lead to deterioration of neurological functions after intracerebral hemorrhage (ICH). Cortical astrocytes are among the most important cells in the central nervous system (CNS), and play key roles in maintaining redox homeostasis by providing oxidative stress defense. Hemin is a product of hemoglobin degradation, which has strong toxicity and can induce reactive oxygen species (ROS). Melatonin (Mel) and its metabolites are well tolerated without toxicity, prevent tissue damage as well as effectively assist in scavenging free radicals. We evaluated the hemin neurotoxicity to astrocytes and the resistance of Mel-treated astrocytes to hemin neurotoxicity. And we found Mel induced PKCα phosphorylation (p-PKC), nuclear translocation of Nrf2 in astrocytes, and upregulation of HO-1, which contributed to the reduction of ROS accumulation and cell apoptosis. Nrf2 and HO1 protein expression upregulated by Mel were decreased after administration of PKC inhibitor, Ro 31-8220 (Ro 31). Luzindole (Luz), a melatonin receptor inhibitor, suppressed p-PKCα, HO-1, and Nrf2 expression upregulated by Mel and increased cell apoptosis rate. The upregulation of HO-1 induced by Mel was depressed by knocking down Nrf2 expression by siRNA, which also decreased the resistance of astrocytes to toxicity of hemin. Mel activates astrocytes through PKCα/Nrf2/HO-1 signaling pathway to acquire resistance to toxicity of hemin and resist from oxidative stress and apoptosis. The positive effect of Mel on PKCα/Nrf2/HO-1 signaling pathway may become a new target for neuroprotection after intracerebral hemorrhage.
氧化应激介导的继发性损伤会导致脑出血（ICH）后神经功能恶化。皮质星形胶质细胞是中枢神经系统（CNS）中最重要的细胞之一，通过提供氧化应激防御在维持氧化还原稳态中发挥关键作用。血红素是血红蛋白降解的产物，具有很强的毒性，可诱导活性氧（ROS）产生。褪黑素（Mel）及其代谢产物耐受性良好且无毒性，可防止组织损伤并有效协助清除自由基。我们评估了血红素对星形胶质细胞的神经毒性以及Mel处理的星形胶质细胞对血红素神经毒性的抗性。我们发现Mel诱导星形胶质细胞中PKCα磷酸化（p-PKC）、Nrf2核转位以及HO-1上调，这有助于减少ROS积累和细胞凋亡。给予PKC抑制剂Ro 31-8220（Ro 31）后，Mel上调的Nrf2和HO1蛋白表达降低。褪黑素受体抑制剂鲁辛朵（Luz）抑制了Mel上调的p-PKCα、HO-1和Nrf2表达，并增加了细胞凋亡率。通过小干扰RNA（siRNA）敲低Nrf2表达可抑制Mel诱导的HO-1上调，这也降低了星形胶质细胞对血红素毒性的抗性。Mel通过PKCα/Nrf2/HO-1信号通路激活星形胶质细胞，以获得对血红素毒性的抗性，并抵抗氧化应激和细胞凋亡。Mel对PKCα/Nrf2/HO-1信号通路的积极作用可能成为脑出血后神经保护的新靶点。
