组蛋白乙酰转移酶抑制剂在慢性疼痛中调制机制及其临床应用

Analgesic effect of histone acetyltransferase inhibitors on chronic pain

背景近年来的研究表明，组蛋白变化的乙酰化和去乙酰化导致了伤害性进展基因的异常转录，而这些基因的异常转录与慢性疼痛紧密相关，并且研究证实炎症和神经损伤上调了组蛋白乙酰转移酶（histone acetyltransferase，HAT），促进了组蛋白的乙酰化进而引起疼痛的发生。据报道，组蛋白乙酰转移酶抑制剂（histone acetvhransferase inhibitor，HATI）能通过阻止趋化因子和环氧化酶-2（cyclooxgenase-2，COX-2）等细胞因子的上调从而缓解疼痛。目的探讨HATI减轻疼痛的机制以及各自的临床应用，完善组蛋白乙酰化和去乙酰化作用于慢性疼痛的理论。内容对目前关于HATI在慢性疼痛治疗中的研究进展进行综述。趋势通过对HATI在慢性疼痛治疗中的研究，为临床镇痛药物的开发提供更多新思路。

Background Recent studies demonstrate that the imbalance between acetylation and deacetylation of histone proteins correlates with abnormal transcription of nociceptive processing genes, strongly associated with the development of inflammatory or neuropathic pain. The treatment of histone acetyltransferase inhibitor （HATI） has been reported to alleviate pain by blocking the upregulation of chemokines and cyclooxygenase-2, and can be a drug target for the treatment of chronic pain. Objective To review the roles of histone acetylation in the development of chronic pain and the application of histone acetyl transferase inhibitors to the treatment of chronic pain. Content In inflammatory and neuropathic pain, over-acetylation of histone protein following the upregulation of histone acetyltransferase （HAT） is associated with pain symptoms. HATI attenuates hyperalgesia probably through inhibiting chemokines, cyclo-oxygenase-2 （COX-2） and cyclin-dependent kinase 5 （Cdk5）. The available HATI include dual substrates inhibitor, derivatives of natural product （such as, garcinia）, small molecule HAT inhibitors （C646）, and inhibitors to bromodomain of HAT. Garcinia has limited water solubility and bioavailability and is difficult to penetrate blood brain barrier. C646, the only HATI with high potency and specificity, is proved to be highly effective to relive pain symptoms. Trend HATI have therapeutic potentials for the treatment of chronic pain. Further investigations are required to develop and validate more HATI.