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Pharmacological augmentation of nicotinamide phosphoribosyltransferase (NAMPT) protects against paclitaxel-induced peripheral neuropathy
eLife ( IF 6.4 ) Pub Date : 2017-11-10 , DOI: 10.7554/elife.29626
Peter M LoCoco 1 , April L Risinger 1 , Hudson R Smith 1 , Teresa S Chavera 1 , Kelly A Berg 1 , William P Clarke 1
Affiliation  

Chemotherapy-induced peripheral neuropathy (CIPN) arises from collateral damage to peripheral afferent sensory neurons by anticancer pharmacotherapy, leading to debilitating neuropathic pain. No effective treatment for CIPN exists, short of dose-reduction which worsens cancer prognosis. Here we report that stimulation of nicotinamide phosphoribosyltransferase (NAMPT) produced robust neuroprotection in an aggressive CIPN model utilizing the frontline anticancer drug, paclitaxel (PTX). Daily treatment of rats with the first-in-class NAMPT stimulator, P7C3-A20, prevented behavioral and histologic indicators of peripheral neuropathy, stimulated tissue NAD recovery, improved general health, and abolished attrition produced by a near maximum-tolerated dose of PTX. Inhibition of NAMPT blocked P7C3-A20-mediated neuroprotection, whereas supplementation with the NAMPT substrate, nicotinamide, potentiated a subthreshold dose of P7C3-A20 to full efficacy. Importantly, P7C3-A20 blocked PTX-induced allodynia in tumored mice without reducing antitumoral efficacy. These findings identify enhancement of NAMPT activity as a promising new therapeutic strategy to protect against anticancer drug-induced peripheral neurotoxicity.



中文翻译:

烟酰胺磷酸核糖基转移酶(NAMPT)的药理增强可预防紫杉醇引起的周围神经病变

化疗引起的周围神经病变(CIPN)是由于抗癌药物疗法对周围传入感觉神经元的附带损害而引起的,从而使神经病变性疼痛变得虚弱。没有有效的CIPN治疗方法,缺乏减少剂量的方法,这会恶化癌症的预后。在这里我们报告,在使用一线抗癌药物紫杉醇(PTX)的激进CIPN模型中,烟酰胺磷酸核糖基转移酶(NAMPT)的刺激产生了强大的神经保护作用。每天使用一流的NAMPT刺激物P7C3-A20来治疗大鼠,可预防周围神经病变的行为和组织学指标,刺激组织NAD恢复,改善总体健康状况,并消除近乎最大耐受剂量的PTX所引起的磨损。抑制NAMPT可以阻断P7C3-A20介导的神经保护作用,而补充NAMPT底物烟酰胺可使亚阈值剂量的P7C3-A20发挥最大作用。重要的是,P7C3-A20可以在肿瘤小鼠体内阻断PTX诱导的异常性疼痛,而不会降低其抗肿瘤功效。这些发现表明,NAMPT活性的增强是一种有前途的新治疗策略,可预防抗癌药诱导的周围神经毒性。

更新日期:2017-11-16
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