Abstract
To investigate the possible role of IL-4 signaling pathway in vincristine-induced peripheral neuropathy. The mouse model of vincristine-induced peripheral neuropathy and interleukin (IL)-4 knockout mice were utilized to investigate the possible role of IL-4 signaling pathway in vincristine-induced peripheral neuropathy. Vincristine induced increased sensitivity to mechanical stimulation was measured by von Frey hair test 7 and 14 days after intraperitoneal administration of 0.1 mg/kg vincristine in mice. Relative expression levels of cytokines were detected by quantitative real-time PCR. STAT6 expression following vincristine treatment was assessed with western blotting. We discovered that IL-4/STAT6 signaling was down-regulated in vincristine-treated mice. Deletion of IL-4 in mice increased the sensitivity to mechanical allodynia. IL-4 knockout mice also produced more pro-inflammatory cytokines, including IL-1β and TNF-α. Notably, co-administration of exogenous recombination IL-4 significantly prevented vincristine-induced mechanical allodynia. Anti-inflammatory cytokine IL-4 protects rodent model from vincristine-induced peripheral neuropathy via the stimulation of IL-4/STAT6 signaling and inhibition of the pro-inflammatory cytokines.
Highlights
Chemotherapeutic drugs such as vincristine, paclitaxel, andoxaliplatin, are widely used to treat several types of malignant tumors
The results showed that endogenous IL-4 mRNA relative expression level was downregulated in vincristine-treated mice compared to vehicle group (Figure 2A)
These results indicating that chemotherapeutic drug vincristine may contribute to peripheral neuropathy by downregulating anti-inflammatoryIL-4 pathway
Summary
Chemotherapeutic drugs such as vincristine, paclitaxel, andoxaliplatin, are widely used to treat several types of malignant tumors. Their clinical use are accompanied by severe side effects, including peripheral neuropathy and chronic neuropathic pain[1]. The vinca alkaloid compound vincristine (VCR), which was originally derived from the madagascar periwinkle plant, is a common chemotherapeutic agent for a variety of malignancies including acute lymphoblastic leukemia, lymphomas, sarcomas, neuroblastoma, and kidney, liver, lung, brain and breast tumors amongst others[2,3]. Vincristine-induced peripheral neuropathy (VIPN), which affects sensory, motor, and autonomic nerves, is often resistant to standard analgesics[4,5,6]. Rodent and cell models of VIPN have been developed to elucidate the underlying mechanisms[1,7], but the exact mechanism is still not completely understood
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