Painful neuropathy is a common adverse effect of oxaliplatin (OXL), a platinum-derivative chemotherapeutic agent. Oxidative stress and mitochondrial dysfunction are key factors contributing to the development of OXL-induced peripheral neuropathy (OIPN). Based on the antioxidant and antinociceptive properties of mesenchymal stem/stromal cells (MSC), the present study tested the hypothesis that MSC induce antinociceptive effects during OIPN by promoting regulation of redox environment and mitochondrial homeostasis in the nociceptive primary afferents. C57Bl/6 mice submitted to the OXL-chronic neuropathy induction protocol by repeated intravenous administration of OXL (1 mg/kg) were evaluated to determine the paw mechanical and thermal nociceptive thresholds using the von Frey filaments and cold plate tests, respectively. Two weeks after the neuropathy induction, mice were treated with bone marrow-derived MSC (), vehicle, or gabapentin (GBP, 70 mg/kg). Four weeks later, mitochondrial morphology, gene expression profile, and oxidative stress markers in the sciatic nerve and dorsal root ganglia (DRG) were evaluated by transmission electron microscopy, RT-qPCR, and biochemical assays, respectively. OXL-treated mice presented behavioral signs of sensory neuropathy, such as mechanical allodynia and thermal hyperalgesia. The behavioral painful neuropathy was completely reverted by a single administration of MSC, while the daily treatment with GBP induced only a short-lived antinociceptive effect. The ultrastructural analysis of the sciatic nerve and DRG of OIPN mice revealed a high proportion of atypical mitochondria in both myelinated and unmyelinated fibers. Importantly, this mitochondrial atypia was strongly reduced in MSC-treated neuropathic mice. Moreover, MSC-treated neuropathic mice showed upregulation of Sod and Nrf2 mRNA in the sciatic nerve and DRG. In line with this result, MSC reduced markers of nitrosative stress and lipid peroxidation in the sciatic nerve and DRG from OIPN mice. Our data suggest that the reestablishment of redox homeostasis in the nociceptive primary afferents is a mechanism by which MSC transplantation reverts the OXL-induced chronic painful neuropathy.

中文翻译：

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在奥沙利铂诱导的慢性周围神经病中，间充质干细胞/基质细胞促进伤害性初级传入神经中氧化还原稳态的重建作为抗伤害机制

疼痛性神经病变是奥沙利铂 (OXL)（一种铂衍生物化疗药物）的常见不良反应。氧化应激和线粒体功能障碍是导致 OXL 诱导的周围神经病变 (OIPN) 发生的关键因素。基于间充质干细胞/基质细胞 (MSC) 的抗氧化和抗伤害特性，本研究测试了以下假设：MSC 通过促进伤害性初级传入神经中氧化还原环境和线粒体稳态的调节，在 OIPN 期间诱导抗伤害作用。通过重复静脉内施用 OXL (1 mg/kg) 对 C57Bl/6 小鼠进行 OXL 慢性神经病诱导方案的评估，分别使用 von Frey 丝和冷板测试来确定爪机械和热伤害感受阈值。诱导神经病变两周后，用骨髓来源的 MSC 治疗小鼠（）、赋形剂或加巴喷丁（GBP，70 mg/kg）。四周后，分别通过透射电子显微镜、RT-qPCR 和生化检测评估坐骨神经和背根神经节 (DRG) 的线粒体形态、基因表达谱和氧化应激标记物。OXL 治疗的小鼠表现出感觉神经病的行为症状，例如机械性异常性疼痛和热痛觉过敏。单次给予 MSC 即可完全恢复行为性疼痛性神经病变，而每日使用 GBP 治疗仅产生短暂的镇痛作用。对 OIPN 小鼠坐骨神经和 DRG 的超微结构分析显示，有髓神经和无髓神经纤维中都存在高比例的非典型线粒体。重要的是，在接受 MSC 治疗的神经病小鼠中，这种线粒体异型性明显减少。此外，MSC 治疗的神经病小鼠的坐骨神经和 DRG 中的Sod和Nrf2 mRNA上调与这一结果一致，MSC 减少了 OIPN 小鼠坐骨神经和 DRG 中亚硝化应激和脂质过氧化的标记物。我们的数据表明，伤害性初级传入神经中氧化还原稳态的重建是 MSC 移植逆转 OXL 诱导的慢性疼痛性神经病的一种机制。