Antimicrotubulin chemotherapeutic agents, including plant-derived vincaalkaloids such as vincristine, can cause peripheral neuropathic pain. Exogenously activated heme oxygenase 1 (HO-1) is a potential therapy for chemotherapy-induced neuroinflammation. In this study, we investigated a role for Nrf2/HO-1/CO in mediating vincristine-induced neuroinflammation by inhibiting connexin 43 (Cx43) production in the spinal cord following the intrathecal application of the HO-1 inducer protoporphyrin IX cobalt chloride (CoPP) or inhibitor protoporphyrin IX zinc (ZnPP), and we analyzed the underlying mechanisms by which levo-corydalmine (l-CDL, a tetrahydroprotoberberine) attenuates vincristine-induced pain. Treatment with levo-corydalmine or oxycodone hydrochloride (a semisynthetic opioid analgesic, used as a positive control) attenuated vincristine-induced persistent pain hypersensitivity and degeneration of the sciatic nerve. In addition, the increased prevalence of atypical mitochondria induced by vincristine was ameliorated by l-CDL in both A-fibers and C-fibers. Next, we evaluated whether nuclear factor E2-related factor 2 (Nrf2), an upstream activator of HO-1, directly bound to the HO-1 promoter sequence and degraded heme to produce carbon monoxide (CO) following stimulation with vincristine. Notably, l-CDL dose-dependently increased HO-1/CO expression by activating Nrf2 to inhibit Cx43 expression in both the spinal cord and in cultured astrocytes stimulated with TNF-α, corresponding to decreased Cx43-mediated hemichannel. Furthermore, l-CDL had no effect on Cx43 following the silencing of the HO-1 gene. Taken together, our findings reveal a novel mechanism by which Nrf2/HO-1/CO mediates Cx43 expression in vincristine-induced neuropathic pain. In addition, the present findings suggest that l-CDL likely protects against nerve damage and attenuates vincristine-induced neuroinflammation by upregulating Nrf2/HO-1/CO to inhibit Cx43 expression.

中文翻译：

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Levo-corydalmine 通过上调 Nrf2/HO-1/CO 通路抑制连接蛋白 43 的表达来减轻长春新碱诱导的小鼠神经性疼痛。

抗微管蛋白化疗剂，包括植物来源的长春花碱，如长春新碱，可引起周围神经性疼痛。外源性激活的血红素加氧酶 1 (HO-1) 是化疗诱导的神经炎症的潜在疗法。在本研究中，我们研究了 Nrf2/HO-1/CO 在鞘内施用 HO-1 诱导剂原卟啉 IX 氯化钴 (CoPP ) 或抑制剂原卟啉 IX 锌 (ZnPP)，我们分析了 levo-corydalmine ( l-CDL，一种四氢原小檗碱）减轻长春新碱引起的疼痛。用左旋紫苏明或盐酸羟考酮（一种半合成阿片类镇痛剂，用作阳性对照）治疗可减轻长春新碱引起的持续性疼痛超敏反应和坐骨神经退化。此外，长春新碱诱导的非典型线粒体增加的患病率被A 纤维和 C 纤维中的l -CDL 改善。接下来，我们评估了核因子 E2 相关因子 2 (Nrf2)（HO-1 的上游激活剂）是否直接与 HO-1 启动子序列结合并在长春新碱刺激后降解血红素以产生一氧化碳 (CO)。值得注意的是，我-CDL 通过激活 Nrf2 来抑制脊髓和用 TNF-α 刺激的培养的星形胶质细胞中的 Cx43 表达，从而剂量依赖性地增加 HO-1/CO 表达，对应于 Cx43 介导的半通道减少。此外，在 HO-1 基因沉默后， l- CDL 对 Cx43 没有影响。总之，我们的研究结果揭示了 Nrf2/HO-1/CO 在长春新碱诱导的神经性疼痛中介导 Cx43 表达的新机制。此外，目前的研究结果表明，l-CDL 可能通过上调 Nrf2/HO-1/CO 以抑制 Cx43 表达来防止神经损伤并减轻长春新碱诱导的神经炎症。