微管结构稳定剂紫杉醇（PTX）是治疗癌症的重要化疗药物，但其常见的副作用末梢神经病变会严重影响患者的功能状态和生活质量。至今未明确NIMA相关激酶2（NEK2）在PTX引起的神经病理性疼痛进展中的机制角色。成年雄性Sprague-Dawley大鼠腹腔注射PTX引起神经病理性疼痛，通过生化分析测量动物的脊神经后根神经节（DRG）中蛋白质表达水平，通过von Frey测试和热板测试评估嗫觉行为。PTX可增加DRG神经元中重要的微管动力学调节因子NEK2的磷酸化，并诱导深层的神经病理性痛觉过敏。PTX激活的磷酸化NEK2（pNEK2）会增加含有jumonji结构域的蛋白JMJD3的表达，该蛋白是组蛋白去甲基化酶蛋白，能够特异地催化Trpv1基因上的抑制性组蛋白标记H3K27me3的去甲基化，从而增强DRG神经元中瞬时受体电位香草酰亚胺亚型1（TRPV1）的表达。此外，pNEK2依赖的PTX反应程序被增强了p90核糖体S6激酶2（RSK2）的磷酸化。相反，脑脊液内注射选择性RSK2激活拮抗剂kaempferol、选择性NEK2抑制剂NCL 00017509、NEK2靶向的siRNA、选择性JMJD3抑制剂GSK-J4或TRPV1受体拮抗剂capsazepine到PTX处理的大鼠中，可扭转神经病理性痛觉过敏，并恢复Trpv1基因的沉默，表明PTX引起的神经病理性疼痛中磷酸化RSK2（pRSK2）、pNEK2、JMJD3、H3K27me3和TRPV1在DRG神经元中的层次结构和相互作用。 DRG神经元中的pRSK2/JMJD3/H3K27me3/TRPV1信号通路在PTX治疗中扮演着重要的调节因子。版权所有©2023年国际麻醉研究学会。

The microtubule-stabilizing drug paclitaxel (PTX) is an important chemotherapeutic agent for cancer treatment and causes peripheral neuropathy as a common side effect that substantially impacts the functional status and quality of life of patients. The mechanistic role for NIMA-related kinase 2 (NEK2) in the progression of PTX-induced neuropathic pain has not been established.Adult male Sprague-Dawley rats intraperitoneally received PTX to induce neuropathic pain. The protein expression levels in the dorsal root ganglion (DRG) of animals were measured by biochemical analyses. Nociceptive behaviors were evaluated by von Frey tests and hot plate tests.PTX increased phosphorylation of the important microtubule dynamics regulator NEK2 in DRG neurons and induced profound neuropathic allodynia. PTX-activated phosphorylated NEK2 (pNEK2) increased jumonji domain-containing 3 (JMJD3) protein, a histone demethylase protein, to specifically catalyze the demethylation of the repressive histone mark H3 lysine 27 trimethylation (H3K27me3) at the Trpv1 gene, thereby enhancing transient receptor potential vanilloid subtype-1 (TRPV1) expression in DRG neurons. Moreover, the pNEK2-dependent PTX response program is regulated by enhancing p90 ribosomal S6 kinase 2 (RSK2) phosphorylation. Conversely, intrathecal injections of kaempferol (a selective RSK2 activation antagonist), NCL 00017509 (a selective NEK2 inhibitor), NEK2-targeted siRNA, GSK-J4 (a selective JMJD3 inhibitor), or capsazepine (an antagonist of TRPV1 receptor) into PTX-treated rats reversed neuropathic allodynia and restored silencing of the Trpv1 gene, suggesting the hierarchy and interaction among phosphorylated RSK2 (pRSK2), pNEK2, JMJD3, H3K27me3, and TRPV1 in the DRG neurons in PTX-induced neuropathic pain.pRSK2/JMJD3/H3K27me3/TRPV1 signaling in the DRG neurons plays as a key regulator for PTX therapeutic approaches.Copyright © 2023 International Anesthesia Research Society.