Transient receptor potential vanilloid 1 activation induces inflammatory cytokine release in corneal epithelium through MAPK signaling

2007 ◽  
Vol 213 (3) ◽  
pp. 730-739 ◽  
Author(s):  
Fan Zhang ◽  
Hua Yang ◽  
Zheng Wang ◽  
Stefan Mergler ◽  
Hongshan Liu ◽  
...  
Keyword(s):  
Corneal Epithelium ◽  
Inflammatory Cytokine ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Mapk Signaling ◽  
Transient Receptor Potential Vanilloid ◽  
Cytokine Release ◽  
Transient Receptor

scholarly journals Suppression of TRPV1/TRPM8/P2Y Nociceptors by Withametelin via Downregulating MAPK Signaling in Mouse Model of Vincristine-Induced Neuropathic Pain

2021 ◽  
Vol 22 (11) ◽  
pp. 6084
Author(s):  
Adnan Khan ◽  
Bushra Shal ◽  
Ashraf Ullah Khan ◽  
Rahim Ullah ◽  
Muhammad Waleed Baig ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Sciatic Nerve ◽  
Transient Receptor Potential ◽  
Purinergic Receptor ◽  
Receptor Potential ◽  
B Cell Lymphoma ◽  
Mapk Signaling ◽  
Transient Receptor Potential Vanilloid ◽  
Transient Receptor

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 administered 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.

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