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：

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烟酰胺磷酸核糖转移酶 (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) 是由抗癌药物治疗对周围传入感觉神经元造成的附带损伤引起的，导致衰弱性神经性疼痛。CIPN 尚无有效治疗方法，除非减少剂量，否则会恶化癌症预后。在这里，我们报告说，在使用一线抗癌药物紫杉醇 (PTX) 的侵袭性 CIPN 模型中，刺激烟酰胺磷酸核糖转移酶 (NAMPT) 产生了强大的神经保护作用。每日使用一流的 NAMPT 刺激剂 P7C3-A20 治疗大鼠，可以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，并消除接近最大耐受剂量的 PTX 产生的损耗。抑制 NAMPT 可阻断 P7C3-A20 介导的神经保护作用，而补充 NAMPT 底物烟酰胺可增强 P7C3-A20 的阈下剂量以发挥全部功效。重要的是，P7C3-A20 可以阻断 PTX 诱导的肿瘤小鼠异常性疼痛，且不会降低抗肿瘤功效。这些发现表明，NAMPT 活性的增强是一种有前途的新治疗策略，可以预防抗癌药物引起的周围神经毒性。