Department of Anesthesiology, Tianjin Baodi Hospital, Baodi Clinical College of Tianjin Medical University, Tianjin, 301800, China.
Department of Anesthesiology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China.
Biomed Pharmacother. 2020 May;125:110003. doi: 10.1016/j.biopha.2020.110003. Epub 2020 Feb 26.
Chemotherapy drugs such as vincristine (Vin) could cause neuropathic pain. However, it is still lack of ideal therapeutic strategy to treat it. Mitochondrial dysfunction has been involved in the pathogenesis of neuropathic pain. The mitochondrial-targeted antioxidant, mitoquinone (MitoQ), is able to modify mitochondrial signaling, showing beneficial effects on various diseases. In the study, we investigated whether MitoQ could regulate Vin-induced neuropathic pain, and the underlying molecular mechanisms. The results showed that MitoQ significantly improved Vin-induced pain hypersensitivity and glial activation in mice. In addition, Vin resulted in severe oxidative stress in spinal cord tissues of mice, which were inhibited by MitoQ treatment through improving Nrf2 (NF-E2-related factor 2) expression in nuclear. Also, MitoQ treatment dose-dependently reduced the expression of pro-inflammatory cytokines, indicating its anti-inflammatory effects. Importantly, Vin stimulation contributed to mitochondrial fission, as evidenced by the increased expression of phosphorylated Drp1 (dynamin related protein 1) and Fis (mitochondrial fission protein 1), whereas mitochondrial fussion was inhibited. However, these effects were notably abrogated by MitoQ, subsequently improving mitochondrial dysfunction. Moreover, neuron death evoked by Vin was significantly rescued by MitoQ treatment. We also observed significantly reduced expression of cleaved Caspase-3 and Bax expression in spinal cord of MitoQ-treated mice with Vin stimulation. In contrast, anti-apoptotic factor Bcl-2 protein levels decreased by Vin were restored by MitoQ. The process of Cyto-c release from mitochondria triggered by Vin was effectively inhibited in mice treated with MitoQ. These in vivo results were further verified in the primary neurons using the in vitro and ex vivo experiments. Furthermore, MitoQ treatment alleviated axonal degeneration and mitochondria dysfunction induced by Vin. Thus, mitoquinone could alleviate vincristine-induced neuropathic pain by inhibiting oxidative stress and apoptosis via the improvement of mitochondrial dysfunction.
化疗药物如长春新碱（Vin）可引起神经性疼痛。然而，目前仍然缺乏理想的治疗方法。线粒体功能障碍已涉及神经性疼痛的发病机制。线粒体靶向抗氧化剂，mitoquinone（MitoQ），能够修饰线粒体信号，对各种疾病具有有益的作用。在研究中，我们研究了 MitoQ 是否可以调节 Vin 诱导的神经性疼痛及其潜在的分子机制。结果表明，MitoQ 显著改善了 Vin 诱导的小鼠疼痛过敏和神经胶质激活。此外，Vin 导致小鼠脊髓组织中严重的氧化应激，而 MitoQ 通过改善核内 Nrf2（NF-E2 相关因子 2）表达来抑制这种应激。此外，MitoQ 治疗剂量依赖性地降低促炎细胞因子的表达，表明其具有抗炎作用。重要的是，Vin 刺激导致线粒体裂变，这表现为磷酸化 Drp1（dynamin 相关蛋白 1）和 Fis（线粒体分裂蛋白 1）的表达增加，而线粒体融合受到抑制。然而，这些作用被 MitoQ 显著阻断，随后改善了线粒体功能障碍。此外，MitoQ 处理显著挽救了由 Vin 刺激引起的神经元死亡。我们还观察到 Vin 刺激的小鼠脊髓中 cleaved Caspase-3 和 Bax 表达明显减少。相反，由 Vin 降低的抗凋亡因子 Bcl-2 蛋白水平被 MitoQ 恢复。从线粒体释放 Cyto-c 的过程被 Vin 有效抑制，在 MitoQ 处理的小鼠中。这些体内结果在使用体外和离体实验的原代神经元中得到进一步验证。此外，MitoQ 治疗减轻了 Vin 诱导的轴突变性和线粒体功能障碍。因此，mitoquinone 通过改善线粒体功能障碍，通过抑制氧化应激和凋亡来减轻长春新碱诱导的神经性疼痛。
