From the Division of Anesthesiology, Critical Care & Pain Medicine, Department of Pain Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Anesth Analg. 2024 Mar 1;138(3):664-675. doi: 10.1213/ANE.0000000000006736. Epub 2023 Dec 18.
Many chemotherapeutic drugs, including paclitaxel, produce neuropathic pain in patients with cancer, which is a dose-dependent adverse effect. Such chemotherapy-induced neuropathic pain (CINP) is difficult to treat with existing drugs. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a major regulator of antioxidative responses and activates phosphorylated Nrf2 (pNrf2). We determined the analgesic effects of bardoxolone methyl (BM), an Nrf2 activator, and the role of pNrf2 on CINP.
CINP was induced in rats by intraperitoneally injecting paclitaxel on 4 alternate days in rats. BM was injected systemically as single or repeated injections after pain fully developed. RNA transcriptome, mechanical hyperalgesia, levels of inflammatory mediators and pNrf2, and location of pNrf2 in the dorsal root ganglia (DRG) were measured by RNA sequencing, von Frey filaments, Western blotting, and immunohistochemistry in rats and human DRG samples. In addition, the mitochondrial functions in 50B11 DRG neuronal cells were measured by fluorescence assay.
Our RNA transcriptome of CINP rats showed a downregulated Nrf2 pathway in the pain condition. Importantly, single and repeated systemic injections of BM ameliorated CINP. Paclitaxel increased inflammatory mediators, but BM decreased them and increased pNrf2 in the DRG. In addition, paclitaxel decreased mitochondrial membrane potential and increased mitochondrial volume in 50B11 cells, but BM restored them. Furthermore, pNrf2 was expressed in neurons and satellite cells in rat and human DRG.
Our results demonstrate the analgesic effects of BM by Nrf2 activation and the fundamental role of pNrf2 on CINP, suggesting a target for CINP and a therapeutic strategy for patients.
许多化疗药物，包括紫杉醇，会在癌症患者中产生神经性疼痛，这是一种剂量依赖性的不良反应。这种化疗诱导的神经性疼痛（CINP）用现有药物很难治疗。核因子红细胞 2 相关因子 2（Nrf2）是抗氧化反应的主要调节剂，并激活磷酸化 Nrf2（pNrf2）。我们确定了 Nrf2 激活剂 bardoxolone 甲基（BM）的镇痛作用及其在 CINP 中的作用。
在大鼠中通过腹腔注射紫杉醇，每 4 天重复一次，在大鼠中诱导 CINP。在疼痛完全出现后，通过单次或重复注射系统地注射 BM。通过 RNA 测序、von Frey 纤维、Western blot 和免疫组织化学，在大鼠和人背根神经节（DRG）样本中测量 RNA 转录组、机械性痛觉过敏、炎症介质和 pNrf2 的水平以及 pNrf2 在 DRG 中的位置。此外，通过荧光测定法测量 50B11DRG 神经元细胞中的线粒体功能。
我们对 CINP 大鼠的 RNA 转录组研究显示，在疼痛状态下 Nrf2 通路下调。重要的是，单次和重复的 BM 全身注射可改善 CINP。紫杉醇增加了炎症介质，但 BM 减少了它们，并增加了 DRG 中的 pNrf2。此外，紫杉醇降低了 50B11 细胞中的线粒体膜电位并增加了线粒体体积，但 BM 恢复了它们。此外，pNrf2 在大鼠和人 DRG 的神经元和卫星细胞中表达。
我们的研究结果表明，通过 Nrf2 激活，BM 具有镇痛作用，pNrf2 在 CINP 中具有基本作用，这为 CINP 提供了一个治疗靶点和治疗策略。
