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Suppression of TRPV1/TRPM8/p2y nociceptors by withametelin via downregulating mapk signaling in mouse model of vincristine-induced neuropathic pain
- Title
- Suppression of TRPV1/TRPM8/p2y nociceptors by withametelin via downregulating mapk signaling in mouse model of vincristine-induced neuropathic pain
- Authors
- Khan A.; Shal B.; Khan A.U.; Ullah R.; Baig M.W.; Ul Haq I.; Seo E.K.; Khan S.
- Ewha Authors
- 서은경
- SCOPUS Author ID
- 서은경
- Issue Date
- 2021
- Journal Title
- International Journal of Molecular Sciences
- ISSN
- 1661-6596
- Citation
- International Journal of Molecular Sciences vol. 22, no. 11
- Keywords
- Bax/Bcl-2; MAPK; Neuropathic pain; TRPV1/TRPM8; Vincristine; Withametelin
- Publisher
- MDPI AG
- Indexed
- SCIE; SCOPUS
- Document Type
- Article
- Abstract
- Vincristine (VCR) is a widely used chemotherapy drug that induced peripheral painful neuropathy. Yet, it still lacks an ideal therapeutic strategy. The transient receptor potential (TRP) channels, purinergic receptor (P2Y), and mitogen-activated protein kinase (MAPK) signaling play a crucial role in the pathogenesis of neuropathic pain. Withametelin (WMT), a potential Phytosteroid isolated from datura innoxa, exhibits remarkable neuroprotective properties. The present investigation was designed to explore the effect of withametelin on VCR-induced neuropathic pain and its underlying molecular mechanism. Initially, the neuroprotective potential of WMT was confirmed against hydrogen peroxide (H2O2 )-induced PC12 cells. To develop potential candidates for neuropathic pain treatment, a VCR-induced neuropathic pain model was established. Vincristine (75 µg/kg) was ad-ministered intraperitoneally (i.p.) for 10 consecutive days (day 1–10) for the induction of neuropathic pain. Gabapentin (GBP) (60 mg/kg, i.p.) and withametelin (0.1 and 1 mg/kg i.p.) treatments were given after the completion of VCR injection on the 11th day up to 21 days. The results revealed that WMT significantly reduced VCR-induced pain hypersensitivity, including mechanical allodynia, cold allodynia, and thermal hyperalgesia. It reversed the VCR-induced histopathological changes in the brain, spinal cord, and sciatic nerve. It inhibited VCR-induced changes in the biochemical composition of the myelin sheath of the sciatic nerve. It markedly downregulated the expression levels of TRPV1 (transient receptor potential vanilloid 1); TRPM8 (Transient receptor potential melastatin 8); and P2Y nociceptors and MAPKs signaling, including ERK (Extracellular Signal-Regulated Kinase), JNK (c-Jun N-terminal kinase), and p-38 in the spinal cord. It suppressed apoptosis by regulating Bax (Bcl2-associated X-protein), Bcl-2 (B-cell-lymphoma-2), and Caspase-3 expression. It considerably attenuated inflammatory cytokines, oxidative stress, and genotoxicity. This study suggests that WMT treatment suppressed vincristine-induced neuropathic pain by targeting the TRPV1/TRPM8/P2Y nociceptors and MAPK signaling. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
- DOI
- 10.3390/ijms22116084
- Appears in Collections:
- 약학대학 > 약학과 > Journal papers
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