From the Department of Medicine, Mackay Medical College, New Taipei, Taiwan.
Institute of Biomedical Sciences, Mackay Medical College, New Taipei City, Taiwan.
Anesth Analg. 2023 Dec 1;137(6):1289-1301. doi: 10.1213/ANE.0000000000006397. Epub 2023 Feb 8.
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.
微管稳定剂紫杉醇（PTX）是癌症治疗的重要化疗药物，会引起周围神经病变，这是一种常见的副作用，会严重影响患者的功能状态和生活质量。丝氨酸/苏氨酸激酶 NIMA 相关激酶 2（NEK2）在紫杉醇诱导的神经性疼痛进展中的机制作用尚未确定。
成年雄性 Sprague-Dawley 大鼠腹腔内给予 PTX 诱导神经性疼痛。通过生化分析测量动物背根神经节（DRG）中的蛋白质表达水平。通过 von Frey 试验和热板试验评估痛觉行为。
PTX 增加了 DRG 神经元中重要微管动力学调节剂 NEK2 的磷酸化，并诱导了严重的神经性痛觉过敏。PTX 激活的磷酸化 NEK2（pNEK2）增加了 jumonji 结构域包含 3（JMJD3）蛋白，一种组蛋白去甲基酶蛋白，特异性催化 TRPV1 基因上抑制性组蛋白标记 H3 赖氨酸 27 三甲基化（H3K27me3）的去甲基化，从而增强 DRG 神经元中瞬时受体电位香草酸亚型 1（TRPV1）的表达。此外，pNEK2 依赖性 PTX 反应程序受增强 p90 核糖体 S6 激酶 2（RSK2）磷酸化的调节。相反，鞘内注射山奈酚（一种选择性 RSK2 激活拮抗剂）、NCL 00017509（一种选择性 NEK2 抑制剂）、靶向 NEK2 的 siRNA、GSK-J4（一种选择性 JMJD3 抑制剂）或辣椒素（TRPV1 受体拮抗剂）到 PTX 处理的大鼠中逆转了神经性痛觉过敏，并恢复了 Trpv1 基因的沉默，表明磷酸化 RSK2（pRSK2）、pNEK2、JMJD3、H3K27me3 和 TRPV1 在 DRG 神经元中在 PTX 诱导的神经性疼痛中的层次结构和相互作用。
DRG 神经元中的 pRSK2/JMJD3/H3K27me3/TRPV1 信号传导是 PTX 治疗方法的关键调节剂。
