Department of Pharmacy and Biotechnology, Alma Mater Studiorum, University of Bologna, Via Irnerio 48, 40126 Bologna, Italy.
Department of Pharmacological and Biomolecular Sciences, University of Milan, Via Vanvitelli 32, 20129 Milan, Italy.
Int J Mol Sci. 2021 Nov 3;22(21):11913. doi: 10.3390/ijms222111913.
Chemotherapy-induced neuropathy (CIN) is a major adverse effect associated with many chemotherapeutics, including bortezomib (BTZ). Several mechanisms are involved in CIN, and recently a role has been proposed for prokineticins (PKs), a chemokine family that induces proinflammatory/pro-algogen mediator release and drives the epigenetic control of genes involved in cellular differentiation. The present study evaluated the relationships between epigenetic mechanisms and PKs in a mice model of BTZ-induced painful neuropathy. To this end, spinal cord alterations of histone demethylase KDM6A, nuclear receptors PPARα/PPARγ, PK2, and pro-inflammatory cytokines IL-6 and IL-1β were assessed in neuropathic mice treated with the PK receptors (PKRs) antagonist PC1. BTZ treatment promoted a precocious upregulation of KDM6A, PPARs, and IL-6, and a delayed increase of PK2 and IL-1β. PC1 counteracted allodynia and prevented the increase of PK2 and of IL-1β in BTZ neuropathic mice. The blockade of PKRs signaling also opposed to KDM6A increase and induced an upregulation of PPAR gene transcription. These data showed the involvement of epigenetic modulatory enzymes in spinal tissue phenomena associated with BTZ painful neuropathy and underline a role of PKs in sustaining the increase of proinflammatory cytokines and in exerting an inhibitory control on the expression of PPARs through the regulation of KDM6A gene expression in the spinal cord.
化疗诱导的周围神经病（CIN）是许多化疗药物，包括硼替佐米（BTZ）的主要不良反应。CIN 的发病机制涉及多个机制，最近有人提出趋化因子家族促动力素（PKs）在其中发挥作用，该家族诱导促炎/致痛介质的释放，并驱动涉及细胞分化的基因的表观遗传控制。本研究在 BTZ 诱导的痛性周围神经病的小鼠模型中评估了表观遗传机制与 PKs 之间的关系。为此，评估了神经病理性小鼠中组蛋白去甲基化酶 KDM6A、核受体 PPARα/PPARγ、PK2 和促炎细胞因子 IL-6 和 IL-1β 的脊髓变化，并用 PK 受体（PKRs）拮抗剂 PC1 处理这些小鼠。BTZ 处理可提前上调 KDM6A、PPARs 和 IL-6，并延迟增加 PK2 和 IL-1β。PC1 拮抗痛觉过敏，并防止 BTZ 周围神经病小鼠中 PK2 和 IL-1β 的增加。PKRs 信号转导的阻断也反对 KDM6A 的增加，并诱导 PPAR 基因转录的上调。这些数据表明，表观遗传调节酶参与与 BTZ 痛性周围神经病相关的脊髓组织现象，并强调 PKs 在维持促炎细胞因子的增加以及通过调节脊髓中 KDM6A 基因表达对 PPARs 的表达发挥抑制作用方面发挥作用。
