Levo-corydalmine Attenuates Vincristine-Induced Neuropathic Pain in Mice by Upregulating the Nrf2/HO-1/CO Pathway to Inh
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ORIGINAL ARTICLE
Levo-corydalmine Attenuates Vincristine-Induced Neuropathic Pain in Mice by Upregulating the Nrf2/HO-1/CO Pathway to Inhibit Connexin 43 Expression Lin Zhou 1 & Luyao Ao 1 & Yunyi Yan 1 & Chengyuan Li 1 & Wanting Li 1 & Anqi Ye 1 & Jihua Liu 2 & Yahui Hu 3 & Weirong Fang 1 & Yunman Li 1
# The American Society for Experimental NeuroTherapeutics, Inc. 2019
Abstract 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 vincristineinduced 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 lCDL 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 HO1 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. Key Words Vincristine . heme oxygenase 1 . connexin-43 . nuclear factor E2-related factor 2 . neuropathic pain
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s13311-019-00784-7) contains supplementary material, which is available to authorized users. * Yahui Hu [email protected]
1
State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Mailbox 207, Tongjiaxiang 24, Nanjing 210009, Jiangsu, People’s Republic of China
2
Biotechnology of Traditional Chinese Medicine, China Pharmaceutical University, Nanjing 211198, People’s Republic of China
3
Department of Pharmacy, Children’s Hospital of Nanjing Medical Univer
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