聚（ADP-核糖）聚合酶（PARP）已在人类癌症中得到广泛研究。最近的研究证实，目前可用的 PARP 抑制剂（Olaparib 或 Veliparib）可为患有紫杉醇诱发的神经性疼痛 (PINP) 的临床患者提供临床缓解作用。然而，PARP 过度激活在 PINP 发生过程中的潜在机制仍有待研究。我们报道了 DNA 氧化损伤的诱导、PARP-1 过度激活以及随后的烟酰胺腺嘌呤二核苷酸 (NAD) 耗竭是 PINP 发病机制中的关键事件。因此，我们开发了Olaparib PROTAC来实现PARP的高效降解。连续鞘内注射 Olaparib PROTAC 通过抑制大鼠体内 PARP-1 的活性来预防 PONP。 PARP-1（而非 PARP-2）被证明是PINP 发展中的关键酶。特异性抑制 PARP-1 部分是通过上调 PINP 大鼠背根神经节和脊髓中 Sirtuin-3 (SIRT3) 的表达和脱乙酰酶活性来增强线粒体氧化还原代谢。此外，NAD水平的增加被发现是PARP-1抑制增强SIRT3活性的关键机制。这些发现为PINP发展中DNA氧化损伤的机制提供了新的见解，并表明PARP-1作为一种临床PINP治疗的可能治疗靶点。© 2024 作者。中枢神经系统科学

Poly (ADP-ribose) polymerase (PARP) has been extensively investigated in human cancers. Recent studies verified that current available PARP inhibitors (Olaparib or Veliparib) provided clinical palliation of clinical patients suffering from paclitaxel-induced neuropathic pain (PINP). However, the underlying mechanism of PARP overactivation in the development of PINP remains to be investigated.We reported induction of DNA oxidative damage, PARP-1 overactivation, and subsequent nicotinamide adenine dinucleotide (NAD+) depletion as crucial events in the pathogenesis of PINP. Therefore, we developed an Olaparib PROTAC to achieve the efficient degradation of PARP. Continuous intrathecal injection of Olaparib PROTAC protected against PINP by inhibiting the activity of PARP-1 in rats. PARP-1, but not PARP-2, was shown to be a crucial enzyme in the development of PINP. Specific inhibition of PARP-1 enhanced mitochondrial redox metabolism partly by upregulating the expression and deacetylase activity of sirtuin-3 (SIRT3) in the dorsal root ganglions and spinal cord in the PINP rats. Moreover, an increase in the NAD+ level was found to be a crucial mechanism by which PARP-1 inhibition enhanced SIRT3 activity.The findings provide a novel insight into the mechanism of DNA oxidative damage in the development of PINP and implicate PARP-1 as a possible therapeutic target for clinical PINP treatment.© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.