Wagner Karen M, Yang Jun, Morisseau Christophe, Hammock Bruce D
Department of Entomology and Nematology and UC Davis Comprehensive Cancer Center, University of California Davis, Davis, CA 95616, USA.
Int J Mol Sci. 2025 Jun 12;26(12):5630. doi: 10.3390/ijms26125630.
Chemotherapy-induced peripheral neuropathy (CIPN) is a painful condition recalcitrant to current available therapies. CIPN pain can be severe and dose-limiting or dose-reducing for life-extending chemotherapeutics and, to date, there is no treatment to alter the progression of CIPN. For these experiments we used docetaxel, a first-line therapy for metastatic prostate cancer in humans and investigated the soluble epoxide hydrolase inhibitor EC5026 for its analgesic efficacy against this CIPN pain. Male SD rats (n = 10/group) were pretreated with 1 mg/kg EC5026 in formulated drinking water or vehicle for one week prior to docetaxel injections. The rats continued the formulated drinking water during three once-a-week docetaxel 10 mg/kg i.p. injections and were maintained on treatment until the end of week 5 when all groups were transitioned to normal drinking water. Nociceptive testing occurred throughout the entire experiment including after transitioning to normal drinking water. EC5026 increased mechanical withdrawal thresholds and latencies on the cold plate compared to docetaxel-treated controls. There were no motor effects of the compound, and the formulated drinking water provided favorable exposure. These results demonstrated that EC5026 administered prophylactically was both analgesic and able to limit the severity of mechanical and cold sensitivities in the docetaxel CIPN rat model.
化疗引起的周围神经病变（CIPN）是一种对现有治疗方法顽固的疼痛病症。CIPN疼痛可能很严重，对于延长生命的化疗药物而言会限制剂量或降低剂量，而且迄今为止，尚无治疗方法可改变CIPN的进展。在这些实验中，我们使用了多西他赛（一种用于人类转移性前列腺癌的一线治疗药物），并研究了可溶性环氧化物水解酶抑制剂EC5026对这种CIPN疼痛的镇痛效果。在注射多西他赛前一周，将雄性SD大鼠（每组10只）用1mg/kg EC5026溶解于配制饮用水或赋形剂中进行预处理。在每周一次腹腔注射10mg/kg多西他赛的三次注射期间，大鼠持续饮用配制饮用水，并持续接受治疗直至第5周末，此时所有组都过渡到正常饮用水。在整个实验过程中，包括过渡到正常饮用水后，都进行伤害性感受测试。与多西他赛治疗的对照组相比，EC5026提高了机械性撤足阈值和冷板潜伏期。该化合物没有运动效应，并且配制饮用水提供了良好的接触途径。这些结果表明，预防性给予EC5026具有镇痛作用，并且能够限制多西他赛CIPN大鼠模型中机械性和冷敏感性的严重程度。
