Department of Anesthesiology, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, NO. 29 Xinglong Road, Changzhou, 213000, Jiangsu, China.
Hum Cell. 2019 Jul;32(3):251-259. doi: 10.1007/s13577-019-00238-4. Epub 2019 Jan 30.
Chemotherapy-induced neuropathic pain (CINP) is a common and debilitating side effect of cancer treatment. Evodiamine, a major effective compound isolated from Evodia rutaecarpa, has been associated with anti-inflammatory and anti-nociceptive effects, an important therapeutic strategy for the treatment of neuropathic pain. However, the effects of evodiamine on CINP remain unknown. Thus, this study aims to investigate the pharmacological potential of evodiamine in attenuating paclitaxel-induced peripheral neuropathy. The results showed that evodiamine enhanced but not reduced the sensitivity of cancer cells to paclitaxel treatment. In a rat model of paclitaxel-induced peripheral neuropathy, evodiamine significantly ameliorated the development of mechanical and thermal hypersensitivity. Moreover, paclitaxel-induced the loss of intraepidermal nerve fibers was markedly inhibited by evodiamine administration. This inhibitory effect was accompanied with the decrease in inflammatory and chemoattractant cytokines level in dorsal root ganglia (DRG), such as interleukin (IL)-1β, IL-6, tumor necrosis factor-α and monocyte chemoattractant protein-1. In addition, evodiamine administration limited paclitaxel-induced elevation of oxidative stress in DRG tissues. The mitochondrial dysfunction evoked by paclitaxel was also remarkably improved in evodiamine-treated rats, evidenced by restoration of peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α), uncoupling protein 2 (UCP2), and superoxide dismutase 2 (SOD2) expression. In in vitro studies, we found that evodiamine prevented paclitaxel-induced the loss of mitochondrial membrane potential and PGC-1α, UCP2 and SOD2 expression in DRG cells. In conclusion, our study demonstrates that evodiamine ameliorates paclitaxel-induced neuropathic pain by inhibiting inflammatory response and maintaining mitochondrial anti-oxidant functions, indicating that evodiamine may be a promising therapeutic agent for CINP treatment.
化疗诱导性神经病理性疼痛（CINP）是癌症治疗的一种常见且使人虚弱的副作用。吴茱萸碱是从吴茱萸中分离得到的主要有效化合物，具有抗炎和抗伤害感受作用，是治疗神经病理性疼痛的重要治疗策略。然而，吴茱萸碱对 CINP 的影响尚不清楚。因此，本研究旨在探讨吴茱萸碱减轻紫杉醇诱导的周围神经病变的药理作用。结果表明，吴茱萸碱增强而非降低了癌细胞对紫杉醇治疗的敏感性。在紫杉醇诱导的周围神经病变大鼠模型中，吴茱萸碱显著改善了机械和热感觉过敏的发展。此外，吴茱萸碱给药显著抑制了紫杉醇诱导的表皮内神经纤维丢失。这种抑制作用伴随着背根神经节（DRG）中炎症和趋化因子水平的降低，如白细胞介素（IL）-1β、IL-6、肿瘤坏死因子-α和单核细胞趋化蛋白-1。此外，吴茱萸碱给药限制了 DRG 组织中紫杉醇诱导的氧化应激升高。用吴茱萸碱处理的大鼠中，紫杉醇引起的线粒体功能障碍也得到了显著改善，表现为过氧化物酶体增殖物激活受体γ共激活因子 1-α（PGC-1α）、解偶联蛋白 2（UCP2）和超氧化物歧化酶 2（SOD2）的表达恢复。在体外研究中，我们发现吴茱萸碱可防止紫杉醇诱导的 DRG 细胞中线粒体膜电位丧失以及 PGC-1α、UCP2 和 SOD2 表达的降低。总之，本研究表明，吴茱萸碱通过抑制炎症反应和维持线粒体抗氧化功能改善紫杉醇诱导的神经病理性疼痛，表明吴茱萸碱可能是治疗 CINP 的一种有前途的治疗剂。
