Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology and Toxicology, Viale G. Pieraccini 6, 50139 Florence, Italy.
Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology and Toxicology, Viale G. Pieraccini 6, 50139 Florence, Italy.
Eur J Pharmacol. 2018 Apr 15;825:99-106. doi: 10.1016/j.ejphar.2018.02.034.
Histone deacetylase inhibitors (HDACIs) interfere with the epigenetic process of histone acetylation and are known to have analgesic properties in models of chronic inflammatory pain. Administration of a selective HDAC1 inhibitor (LG325) in SNI-subjected mice significantly attenuated behavior related to injury-induced pain. Understanding the HDAC1 pathway in epigenetic regulation of pathological pain is of great medical relevance. Spared nerve injury (SNI) mice showed a significant increase in the HDAC1 protein levels within spinal cord in coincidence with the nociceptive phenotype at 1 and 3 weeks after nerve injury. No variation in HDAC3, DNMT3a, AcH3, MBD3 and MeCP2 levels was detected. Increased expression of HDAC1 is accompanied by activation of the JNK-c-Jun signaling pathway. A robust spinal JNK-1 overphosphorylation was observed post nerve-injury along with a selective JNK-dependent increase in p-c-Jun and HDAC1 protein levels. Co-immunoprecipitation experiments showed the presence of a heterodimeric complex between HDAC1 and c-Jun in SNI mice indicating that these transcription factors can act together to regulate transcription through heterodimerization. Stimulation of c-Jun phosphorylation was prevented by the selective HDAC1 inhibitor LG325. We found that HDAC1 was associated with c-Jun in nuclei of spinal dorsal horn astrocytes expressing JNK. On the other hand, the presence of HDAC1 and c-Jun interaction was not detected in control mice. These findings provide new insights into the mechanisms underlying the anti-nociceptive activity of HDAC inhibitors. Taken together, these data support a role for histone deacetylase in the emergence of neuropathic pain.
组蛋白去乙酰化酶抑制剂 (HDACIs) 干扰组蛋白乙酰化的表观遗传过程，已知在慢性炎症性疼痛模型中具有镇痛作用。在 SNI 处理的小鼠中给予选择性 HDAC1 抑制剂 (LG325) 可显著减轻与损伤诱导性疼痛相关的行为。了解组蛋白去乙酰化酶 1 通路在病理性疼痛的表观遗传调控中的作用具有重要的医学相关性。在神经损伤后 1 周和 3 周，与伤害感受表型一致，SNI 小鼠脊髓内 HDAC1 蛋白水平显著增加。未检测到 HDAC3、DNMT3a、AcH3、MBD3 和 MeCP2 水平的变化。HDAC1 的表达增加伴随着 JNK-c-Jun 信号通路的激活。神经损伤后观察到 JNK-1 过度磷酸化，同时选择性 JNK 依赖性 p-c-Jun 和 HDAC1 蛋白水平增加。共免疫沉淀实验显示，在 SNI 小鼠中存在 HDAC1 和 c-Jun 之间的异二聚体复合物，表明这些转录因子可以通过异二聚化共同作用来调节转录。选择性 HDAC1 抑制剂 LG325 可阻止 c-Jun 磷酸化。我们发现，在表达 JNK 的脊髓背角星形胶质细胞核中，HDAC1 与 c-Jun 相关。另一方面，在对照小鼠中未检测到 HDAC1 和 c-Jun 相互作用的存在。这些发现为 HDAC 抑制剂的抗伤害感受活性的机制提供了新的见解。总之，这些数据支持组蛋白去乙酰化酶在神经病理性疼痛出现中的作用。
