背景:紫杉烷类如紫杉醇(PTX)诱导剂量依赖性化疗诱导的周围神经病变(CIPN),这与使人衰弱的慢性疼痛和步态障碍有关。据报道,巨噬细胞相关的促炎活性增加可介导神经性疼痛的发展和维持。虽然脊髓刺激(SCS)已用于许多疼痛病症,支持其用于CIPN的机制仍有待阐明。因此,我们的目的是研究SCS是否可以减轻PTX诱导的步态损伤和机械超敏反应的Rowlette裸(RNU)大鼠的坐骨神经中的雪旺细胞介导的和巨噬细胞介导的神经炎症。
方法:将成年雄性荷瘤RNU大鼠用于本研究,检查PTX治疗和SCS。每周评估步态和机械超敏反应。细胞因子,基因表达,巨噬细胞浸润和极化,神经形态学和雪旺氏细胞在坐骨神经使用多重免疫分析检查,批量RNA测序,组织化学和免疫组织化学技术。
结果:SCS(50Hz,0.2毫秒,80%运动阈值)减弱了机械超敏反应的发展(20.93±0.80vs12.23±2.71克,p<0.0096)和颞步态障碍[摆动(90.41±7.03vs117.27±9.71%,p<0.0076),和单次站立次数(94.92±3.62vs112.75±7.27%,p<0.0245)]由PTX诱导(SCS+PTX+肿瘤vs假SCS+PTX+肿瘤)。SCS还减弱了施万细胞的减少,髓鞘厚度和抗炎细胞因子白细胞介素(IL)-10的浓度增加。大量RNA测序显示SCS后差异基因表达,607个(59.2%)基因上调,而418个(40.8%)基因下调。值得注意的是,与抗炎细胞因子和神经元生长相关的基因上调,而与促炎基因相关的基因,M2γ极化增加,巨噬细胞浸润减少和雪旺氏细胞丢失下调。
结论:SCS可以减轻PTX引起的疼痛和颞步态障碍,这可能部分归因于坐骨神经中雪旺氏细胞损失和巨噬细胞介导的神经炎症的减少。
BACKGROUND: Taxanes such as paclitaxel (PTX) induce dose-dependent chemotherapy-induced peripheral neuropathy (CIPN), which is associated with debilitating chronic pain and gait impairment. Increased macrophage-related proinflammatory activities have been reported to mediate the development and maintenance of neuropathic pain. While spinal cord stimulation (SCS) has been used for a number of pain conditions, the mechanisms supporting its use for CIPN remain to be elucidated. Thus, we aimed to examine whether SCS can attenuate Schwann cell-mediated and macrophage-mediated neuroinflammation in the sciatic nerve of Rowlette Nude (RNU) rats with PTX-induced gait impairment and mechanical hypersensitivity.
METHODS: Adult male tumor-bearing RNU rats were used for this study examining PTX treatment and SCS. Gait and mechanical hypersensitivity were assessed weekly. Cytokines, gene expression, macrophage infiltration and polarization, nerve morphology and Schwann cells were examined in sciatic nerves using multiplex immunoassay, bulk RNA sequencing, histochemistry and immunohistochemistry techniques.
RESULTS: SCS (50 Hz, 0.2 milliseconds, 80% motor threshold) attenuated the development of mechanical hypersensitivity (20.93±0.80 vs 12.23±2.71 grams, p<0.0096) and temporal gait impairment [swing (90.41±7.03 vs 117.27±9.71%, p<0.0076), and single stance times (94.92±3.62 vs 112.75±7.27%, p<0.0245)] induced by PTX (SCS+PTX+Tumor vs Sham SCS+PTX+Tumor). SCS also attenuated the reduction in Schwann cells, myelin thickness and increased the concentration of anti-inflammatory cytokine interleukin (IL)-10. Bulk RNA sequencing revealed differential gene expression after SCS, with 607 (59.2%) genes upregulated while 418 (40.8%) genes were downregulated. Notably, genes related to anti-inflammatory cytokines and neuronal growth were upregulated, while genes related to proinflammatory-promoting genes, increased M2γ polarization and decreased macrophage infiltration and Schwann cell loss were downregulated.
CONCLUSIONS: SCS may attenuate PTX-induced pain and temporal gait impairment, which may be partly attributed to decreases in Schwann cell loss and macrophage-mediated neuroinflammation in sciatic nerves.