Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology and Toxicology, University of Florence, Viale G. Pieraccini 6, 50139, Florence, Italy.
Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology and Toxicology, University of Florence, Viale G. Pieraccini 6, 50139, Florence, Italy.
Pharmacol Res. 2021 Mar;165:105431. doi: 10.1016/j.phrs.2021.105431. Epub 2021 Jan 30.
Current treatments for neuropathic pain have often moderate efficacy and present unwanted effects showing the need to develop effective therapies. Accumulating evidence suggests that histone acetylation plays essential roles in chronic pain and the analgesic activity of histone deacetylases (HDACs) inhibitors is documented. Bromodomain and extra-terminal domain (BET) proteins are epigenetic readers that interact with acetylated lysine residues on histones, but little is known about their implication in neuropathic pain. Thus, the current study was aimed to investigate the effect of the combination of HDAC and BET inhibitors in the spared nerve injury (SNI) model in mice. Intranasal administration of i-BET762 (BET inhibitor) or SAHA (HDAC inhibitor) attenuated thermal and mechanical hypersensitivity and this antiallodynic activity was improved by co-administration of both drugs. Spinal cord sections of SNI mice showed an increased expression of HDAC1 and Brd4 proteins and combination produced a stronger reduction compared to each epigenetic agent alone. SAHA and i-BET762, administered alone or in combination, counteracted the SNI-induced microglia activation by inhibiting the expression of IBA1, CD11b, inducible nitric oxide synthase (iNOS), the activation of nuclear factor-κB (NF-κB) and signal transducer and activator of transcription-1 (STAT1) with comparable efficacy. Conversely, the epigenetic inhibitors showed a modest effect on spinal proinflammatory cytokines content that was significantly potentiated by their combination. Present results indicate a key role of acetylated histones and their recruitment by BET proteins on microglia-mediated spinal neuroinflammation. Targeting neuropathic pain with the combination of HDAC and BET inhibitors may represent a promising new therapeutic option.
目前治疗神经性疼痛的方法往往疗效中等，且存在不良反应，这表明需要开发有效的治疗方法。越来越多的证据表明，组蛋白乙酰化在慢性疼痛和组蛋白去乙酰化酶（HDAC）抑制剂的镇痛活性中发挥着重要作用。溴结构域和末端结构域（BET）蛋白是表观遗传阅读器，与组蛋白上的乙酰化赖氨酸残基相互作用，但它们在神经性疼痛中的作用知之甚少。因此，本研究旨在研究 HDAC 和 BET 抑制剂联合应用于 spared nerve injury (SNI) 小鼠模型的效果。鼻内给予 i-BET762（BET 抑制剂）或 SAHA（HDAC 抑制剂）可减轻热和机械性超敏反应，两种药物联合给药可改善这种抗痛觉过敏作用。SNI 小鼠脊髓切片显示 HDAC1 和 Brd4 蛋白表达增加，联合用药比单独使用每种表观遗传药物产生更强的降低作用。SAHA 和 i-BET762 单独或联合给药可通过抑制 IBA1、CD11b、诱导型一氧化氮合酶（iNOS）、核因子-κB（NF-κB）和信号转导和转录激活因子-1（STAT1）的表达，抑制 SNI 诱导的小胶质细胞激活，具有相当的疗效。相反，表观遗传抑制剂对脊髓前炎性细胞因子含量的影响较小，但其联合应用可显著增强其作用。目前的结果表明，乙酰化组蛋白及其被 BET 蛋白募集在小胶质细胞介导的脊髓神经炎症中起着关键作用。用 HDAC 和 BET 抑制剂联合治疗神经性疼痛可能是一种很有前途的新治疗选择。
