• Xing Wei, Lijun Jia, Yaqing Zhou, Weimiao Li, Changyou Shan, Shuqun Zhang, and Yonglin Zhao.
• Department of Gynaecology and Obstetrics, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China.
• Pain Res Manag. 2023 Jan 1; 2023: 90587749058774.

ObjectivePaclitaxel-induced peripheral neuropathy (PIPN) is a debilitating and difficult-to-treat side effect of paclitaxel. Soluble epoxide hydrolase (sEH) can rapidly metabolize the endogenous anti-inflammatory mediators' epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acids. This study aimed to assess whether the sEH inhibitor N-(1-(1-oxopropy)-4-piperidinyl]-N'-(trifluoromethoxy) phenyl)-urea (TPPU) plays a critical role in PIPN of rats and provides a new target for treatment.MethodsA Sprague-Dawley male rat model of PIPN induced by nab-paclitaxel was established. Rats were randomly divided into a control group, nab-paclitaxel group, and nab-paclitaxel + TPPU (sEH inhibitor) group, with 36 rats in each group. The effects of the sEH inhibitor TPPU on behavioural assays, apoptosis, glial activation, axonal injury, microstructure, and permeability of the blood-spinal cord barrier were detected, and the underlying mechanisms were explored by examining the expression of NF-κB signalling pathways, inflammatory cytokines, and oxidative stress.ResultsThe results showed that the mechanical and thermal pain thresholds of rats were decreased after nab-paclitaxel treatment, accompanied by an increased expression of axonal injury-related proteins, enhanced cell apoptosis, aggravated destruction of vascular permeability, intense glial responses, and elevated inflammatory cytokines and oxidative stress in the L4-L6 spinal cord. TPPU restored the mechanical and thermal thresholds, decreased cell apoptosis, alleviated axonal injury and glial responses, and protected vascular permeability by increasing the expression of tight junction proteins. TPPU relieved PIPN by inhibiting the activation of the sEH and NF-κB signalling pathways by decreasing the levels of inflammatory cytokines and oxidative stress.ConclusionThese findings support a role for sEH in PIPN and suggest that the inhibition of sEH represents a potential new therapeutic target for PIPN.Copyright © 2023 Xing Wei et al.

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