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 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.
Highlights
Neuropathic pain, referred to as nerve pain, results from different types of nerve injuries, such as chemotherapy-induced neuropathy, traumatic nerve injury, post-herpetic neuralgia, and diabetic neuropathy [1,2]
The results indicated that a vincristine injection induced a marked (p < 0.001) increase in TRPV1/TRPM8/P2Y immunoreactivity compared to the control group
These results suggest that the downregulation of the mRNA expression levels of the TRPV1/TRPM8/P2Y and Jun N-terminal kinase (JNK) proteins by WMT in the spinal cord are likely to have an important role in the amelioration of VCR-induced painful neuropathy
Summary
Neuropathic pain, referred to as nerve pain, results from different types of nerve injuries, such as chemotherapy-induced neuropathy, traumatic nerve injury, post-herpetic neuralgia, and diabetic neuropathy [1,2]. Vincristine (VCR) is an effective chemotherapeutic drug indicated in the treatment of many types of cancer, such as lymphomas, leukemia, breast cancer, and brain tumors [4]. VCR-induced neuropathy is a major dose-limiting side effect and causes the premature termination of cancer therapy and, results in a great impact on the survival of cancer patients [5]. The therapeutic strategies used against VCR-induced neuropathic pain are limited to anticonvulsants, opioids, and tricyclic antidepressants. These treatments are associated with a wide spectrum of adverse effects that limit their satisfactory clinical use in the amelioration of peripheral neuropathy [2]. Novel drugs or therapies that suppress CIPN caused by vincristine without attenuating its anticancer effects are urgently required
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