Department of Painless Endoscopy, People's Hospital of Linzi District, Zibo City, Affiliated Hospital of Binzhou Medical University, Shandong Province, 255400, China.
Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250021, China.
Biochem Biophys Res Commun. 2020 Nov 5;532(2):271-279. doi: 10.1016/j.bbrc.2020.06.142. Epub 2020 Aug 29.
Vincristine (VCR) is a well-known anticancer drug, and frequently causes painful neuropathy and impairs the quality of life of patients. However, the molecular mechanisms revealing VCR-induced neuropathy are still unclear, and effectively therapeutic strategy is still necessary. Bromodomain-containing protein 4 (BRD4) has long been implicated in many different pathological processes, in particular, the development of oxidative stress and inflammation. In the present study, we showed that BRD4 played a mechanistic role in VCR-induced peripheral neuropathy. Using the in vivo transfection of BRD4 siRNA, we found that BRD4 suppression markedly alleviated VCR-induced neuropathic pain. Macrophage infiltration in sciatic nerve was effectively inhibited in VCR-challenged mice with BRD4 knockdown, as evidenced by the markedly reduced expression of F4/80. In the VCR-induced sciatic nerve tissues, we found that the mRNA and protein expression levels of C-X3-C motif chemokine receptor 1 (CX3CR1) and C-C chemokine receptor type 2 (CCR2) were greatly elevated, which were, however, mitigated by siBRD4 injection. In addition, oxidative stress induced by VCR was markedly restrained in sciatic nerve from mice with BRD4 knockdown, which was closely associated with the improved activation of nuclear factor erythroid 2-related factor 2 (Nrf-2) signaling. The in vitro studies indicated that in HO-stimulated primary neurons, BRD4 silence markedly reduced reactive oxygen species (ROS) production and improved Nrf-2 activation, exhibiting anti-oxidant effects. Finally, BRD4 selective inhibitor JQ1 was subjected to mice challenged with VCR. The results confirmed that reducing BRD4 expression by JQ1 effectively ameliorated VCR-induced peripheral neuropathy also through repressing macrophage infiltration, inflammatory response and oxidative stress. Taken together, these findings demonstrated that BRD4 played a critical role in VCR-induced neuropathy, and developing novel and new therapies might be effective for the treatment of VCR-induced neuropathic pain.
长春新碱（VCR）是一种著名的抗癌药物，常导致痛性周围神经病，损害患者的生活质量。然而，揭示长春新碱诱导的周围神经病的分子机制仍不清楚，仍然需要有效的治疗策略。溴结构域蛋白 4（BRD4）长期以来一直与许多不同的病理过程有关，特别是氧化应激和炎症的发展。在本研究中，我们表明 BRD4 在长春新碱诱导的周围神经病变中发挥机制作用。通过体内转染 BRD4 siRNA，我们发现 BRD4 抑制显著缓解长春新碱诱导的神经病理性疼痛。BRD4 敲低的长春新碱处理的小鼠坐骨神经中巨噬细胞浸润得到有效抑制，F4/80 的表达明显减少。在长春新碱诱导的坐骨神经组织中，我们发现 C-X3-C 趋化因子受体 1（CX3CR1）和 C-C 趋化因子受体 2（CCR2）的 mRNA 和蛋白表达水平显著升高，但 siBRD4 注射可减轻其升高。此外，BRD4 敲低可明显抑制长春新碱诱导的坐骨神经中的氧化应激，这与核因子红细胞 2 相关因子 2（Nrf-2）信号的激活改善密切相关。体外研究表明，在 HO 刺激的原代神经元中，BRD4 沉默可显著减少活性氧（ROS）的产生并改善 Nrf-2 的激活，从而发挥抗氧化作用。最后，BRD4 选择性抑制剂 JQ1 用于长春新碱处理的小鼠。结果证实，通过 JQ1 降低 BRD4 表达可有效改善长春新碱诱导的周围神经病，也可通过抑制巨噬细胞浸润、炎症反应和氧化应激。总之，这些发现表明 BRD4 在长春新碱诱导的神经病中起关键作用，开发新的治疗方法可能对治疗长春新碱诱导的神经病理性疼痛有效。
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