Levo-corydalmine Attenuates Vincristine-Induced Neuropathic Pain in Mice by Upregulating the Nrf2/HO-1/CO Pathway to Inhibit Connexin 43 Expression

被引:0
作者
Lin Zhou
Luyao Ao
Yunyi Yan
Chengyuan Li
Wanting Li
Anqi Ye
Jihua Liu
Yahui Hu
Weirong Fang
Yunman Li
机构
[1] China Pharmaceutical University,State Key Laboratory of Natural Medicines, Department of Physiology
[2] China Pharmaceutical University,Biotechnology of Traditional Chinese Medicine
[3] Children’s Hospital of Nanjing Medical University,Department of Pharmacy
来源
Neurotherapeutics | 2020年 / 17卷
关键词
Vincristine; heme oxygenase 1; connexin-43; nuclear factor E2-related factor 2; neuropathic pain;
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摘要
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.
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页码:340 / 355
页数:15
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