HDAC inhibitors as cognitive enhancers in fear, anxiety and trauma therapy: where do we stand?
HDAC inhibitors as cognitive enhancers in fear, anxiety and trauma therapy: where do we stand?
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DOI：
10.1042/bst20130233
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发表时间：
2014-04
影响因子：
3.9
通讯作者：
Singewald N
中科院分区：
文献类型：
--
作者：
Whittle N;Singewald N
治疗焦虑症、恐慌症和创伤后应激障碍（PTSD）等焦虑和恐惧相关疾病的新策略是将 CBT（认知行为疗法）（包括基于消退的暴露疗法）与认知增强剂相结合。通过针对和促进学习的机制，该领域的药物开发旨在设计 CBT 增强化合物，帮助克服消退学习缺陷，促进长期恐惧抑制，从而支持预防复发。揭示与消退记忆生成相关的特定基因的表观遗传调控作用的进展为这个方向开辟了新的途径。本综述审查了临床前研究的最新证据，表明通过遗传或药理学抑制 HDAC（组蛋白脱乙酰酶）来增加组蛋白乙酰化，例如通过伏立诺他/SAHA（辛二酰苯胺异羟肟酸）、恩替司他/MS-275、丁酸钠、TSA（曲古抑菌素A）或VPA（丙戊酸），或通过靶向HAT（组蛋白乙酰转移酶），增强恐惧消退，重要的是，产生长期消退记忆，可以防止恐惧现象再次出现。涉及 BDNF（脑源性神经营养因子）和 NMDA（N-甲基-D-天冬氨酸）受体信号传导的分子机制和途径刚刚开始被揭示。对健康人类的首次研究支持 HDAC 抑制剂的促进消退作用。最近的证据表明，HDAC 抑制剂可以挽救灭绝记忆受损的啮齿类动物的缺陷，表明这种方法对于暴露疗法耐药的患者也具有潜在的临床效用。未来的重要工作包括研究 HDAC 抑制剂治疗的长期安全性以及同种型特异性抑制剂的设计。总而言之，HDAC 抑制剂显示出作为药理学辅助剂的巨大潜力，可增强基于暴露的方法在焦虑和创伤治疗中的功效。
A novel strategy to treat anxiety and fear-related disorders such as phobias, panic and PTSD (post-traumatic stress disorder) is combining CBT (cognitive behavioural therapy), including extinction-based exposure therapy, with cognitive enhancers. By targeting and boosting mechanisms underlying learning, drug development in this field aims at designing CBT-augmenting compounds that help to overcome extinction learning deficits, promote long-term fear inhibition and thus support relapse prevention. Progress in revealing the role of epigenetic regulation of specific genes associated with extinction memory generation has opened new avenues in this direction. The present review examines recent evidence from pre-clinical studies showing that increasing histone acetylation, either via genetic or pharmacological inhibition of HDACs (histone deacetylases) by e.g. vorinostat/SAHA (suberoylanilide hydroxamic acid), entinostat/MS-275, sodium butyrate, TSA (trichostatin A) or VPA (valproic acid), or by targeting HATs (histone acetyltransferases), augments fear extinction and, importantly, generates a long-term extinction memory that can protect from return of fear phenomena. The molecular mechanisms and pathways involved including BDNF (brain-derived neurotrophic factor) and NMDA (N-methyl-D-aspartate) receptor signalling are just beginning to be revealed. First studies in healthy humans are in support of extinction-facilitating effects of HDAC inhibitors. Very recent evidence that HDAC inhibitors can rescue deficits in extinction-memory-impaired rodents indicates a potential clinical utility of this approach also for exposure therapy-resistant patients. Important future work includes investigation of the long-term safety aspects of HDAC inhibitor treatment, as well as design of isotype(s)-specific inhibitors. Taken together, HDAC inhibitors display promising potential as pharmacological adjuncts to augment the efficacy of exposure-based approaches in anxiety and trauma therapy.