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Neuropharmacology. 2018 Jun;135:34-47. doi: 10.1016/j.neuropharm.2018.03.004. Epub 2018 Mar 5.

Levo-corydalmine alleviates vincristine-induced neuropathic pain in mice by inhibiting an NF-kappa B-dependent CXCL1/CXCR2 signaling pathway.

Author information

1
State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Nanjing 210009, PR China.
2
Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing, 210004, PR China.
3
Biotechnology of Traditional Chinese Medicine, China Pharmaceutical University, Nanjing, 211198, PR China.
4
State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: weirongfang@163.com.
5
Biotechnology of Traditional Chinese Medicine, China Pharmaceutical University, Nanjing, 211198, PR China. Electronic address: jihualiu88@163.com.
6
State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: yunmanlicpu@hotmail.com.

Abstract

Vincristine is a commonly used chemotherapeutic drug that can produce painful peripheral neuropathy. The chemokine (C-X-C motif) ligand 1 (CXCL1) and its receptor chemokine (C-X-C motif) receptor 2 (CXCR2) may mediate the resolution of this inflammation. In this study, we investigated whether and how CXCL1 contributes to vincristine-induced pain and the underlying mechanisms of levo-corydalmine (l-CDL, a tetrahydroprotoberberine). Oxycodone hydrochloride (a semisynthetic opioid analgesic) was used as positive control in vivo experiments. The results revealed that both l-CDL and oxycodone attenuated vincristine-induced persistent pain hypersensitivity and proinflammatory factors release in mice. CXCL1 and CXCR2 were increased from 6 to 14 days after vincristine administration in the spinal cord. In addition, vincristine injection induced the phosphorylation of NFκB by activating p65/RelA. To confirm these results, we demonstrated that l-CDL controlled astrocytic-released CXCL1 by inhibiting p65/RelA activation, thus acting on the CXCR2 receptor in the spinal cord. In cultured astrocytes, TNF-α elicited marked release of the chemokine CXCL1; moreover, the release was blocked by NFκB p65 small interfering RNA, NFκB inhibitor, and was dose-dependently decreased by l-CDL. However, l-CDL had no effect on CXCL1 in response to NFκB p65-silenced. In primary neurons, l-CDL indirectly reduced an increase in CXCR2 by astrocyte-conditioned medium but did not act directly on the CXCR2 site. Taken together, our data first demonstrate that an NFκB-dependent CXCL1/CXCR2 signaling pathway is involved in vincristine-induced neuropathic pain. In addition, the present findings suggest that l-CDL likely attenuates this inflammation through down-regulation of this signaling pathway.

KEYWORDS:

CXCL1; CXCR2; NF-kappa B (NFκB); Neuropathic pain; Vincristine

[Indexed for MEDLINE]

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