The involvement of autophagic flux in the development and recovery of doxorubicin-induced neurotoxicity.
The involvement of autophagic flux in the development and recovery of doxorubicin-induced neurotoxicity.
复制标题
自噬流参与阿霉素诱导的神经毒性的发生和恢复。
DOI：
10.1016/j.freeradbiomed.2018.10.418
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发表时间：
2018
影响因子：
7.4
通讯作者：
Jiang Pei
中科院分区：
文献类型：
--
作者：
Zhou Xueyuan;Xu Pengfei;Dang Ruili;Guo Yujin;Li Gongying;Qiao Yi;Xie Ruining;Liu Yuanyuan;Jiang Pei
多柔比星（Dox）是一种有效的抗肿瘤药物，但其对非靶组织尤其是心脑组织的细胞毒性限制了其临床应用。药物引起的神经元损伤主要是由氧化应激介导的，其中自噬起着核心作用。尽管大量研究表明自噬参与神经退行性疾病和脑损伤，但关于Dox诱导的神经元死亡中自噬过程的证据有限。我们发现，重复Dox给药诱导LC 3 II和P62的蛋白表达和受损的自噬通量与增强的自噬体积累在大鼠海马中，而停止Dox治疗两周后，自噬过程恢复，甚至刺激，与正常的蛋白水平的LC 3 II和P62和Becline-1的表达增强，表明在恢复状态的代偿反应。同样，虽然重复Dox暴露抑制海马溶酶体相关膜蛋白2（LAMP 2）和组织蛋白酶D（CTSD）的表达，并抑制CTSD活性，但在恢复两周后，大鼠中Dox诱导的受损自噬-溶酶体途径也恢复。为了进一步验证自噬的作用，在两周的恢复期内每天给予自噬抑制剂3-甲基腺嘌呤（3-MA）。我们的数据表明，虽然在恢复状态下的动物表现出显着的趋势，减少氧化损伤，正常的抗氧化系统和改善内质网（ER）的压力相比，Dox诱导的毒性模型，3-MA治疗废除恢复过程，导致持续的氧化和ER应激和神经细胞凋亡。总的来说，本研究首次提供了自噬参与Dox诱导的神经毒性的发展和恢复的证据，突出了减轻化疗诱导的神经元损伤的新靶点。
Doxorubicin (Dox) is an effective anti-cancer agent, whose clinical use is limited by the cytotoxicity in non-target tissues, especially the heart and brain. The drug-induced neuronal damage is primarily mediated by oxidative stress, in which autophagy plays a central role. Although numerous studies indicate the involvement of autophagy in neurodegenerative diseases and brain injury, the evidence concerning autophagic process in Dox-induced neuronal death is limited. We found that repeated Dox administration induced the protein expression of LC3II and P62 and impaired autophagic flux with enhanced autophagasome accumulation in rat hippocampus, whereas two weeks after the cessation of Dox treatment, the autophagic process was restored, even stimulated, with normalized protein levels of LC3II and P62 and enhanced expression of Becline-1, indicating a compensatory response in the recovery state. Likewise, while repeated Dox exposure inhibited the hippocampal expression of lysosomal-associated membrane protein 2 (LAMP2) and cathepsin D (CTSD), and suppressed CTSD activity, the Dox-induced impaired autophagy-lysosome pathway was also restored in rats following two weeks of recovery. To further verify the role of autophagy, the autophagy inhibitor, 3-methyladenine (3-MA), was administrated daily for the two weeks of recovery period. Our data demonstrated that while the animals in the recovery state showed a significant trend to decreased oxidative damage, normalized antioxidative system and ameliorated endoplasmic reticulum (ER) stress compared with Dox-induced toxic model, 3-MA treatment abrogated the recovering process, resulting in sustained oxidative and ER stress and neuronal apoptosis. Collectively, the present study firstly provided the evidence for the involvement of autophagy in both development and recovery of Dox-induced neurotoxicity, highlighting a novel target for mitigating the chemotherapy-induced neuronal damage.