作为酒精药物疗法靶点的转录调节因子
Transcriptional Regulators as Targets for Alcohol Pharmacotherapies.
作者信息
Savarese Antonia M, Lasek Amy W
机构信息
Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, USA.
Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, OR, USA.
出版信息
Handb Exp Pharmacol. 2018;248:505-533. doi: 10.1007/164_2018_101.
Alcohol use disorder (AUD) is a chronic relapsing brain disease that currently afflicts over 15 million adults in the United States. Despite its prevalence, there are only three FDA-approved medications for AUD treatment, all of which show limited efficacy. Because of their ability to alter expression of a large number of genes, often with great cell-type and brain-region specificity, transcription factors and epigenetic modifiers serve as promising new targets for the development of AUD treatments aimed at the neural circuitry that underlies chronic alcohol abuse. In this chapter, we will discuss transcriptional regulators that can be targeted pharmacologically and have shown some efficacy in attenuating alcohol consumption when targeted. Specifically, the transcription factors cyclic AMP-responsive element binding protein (CREB), peroxisome proliferator-activated receptors (PPARs), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and glucocorticoid receptor (GR), as well as the epigenetic enzymes, the DNA methyltransferases (DNMTs) and histone deacetylases (HDACs), will be discussed.
酒精使用障碍（AUD）是一种慢性复发性脑部疾病，目前在美国折磨着超过1500万成年人。尽管其患病率很高，但美国食品药品监督管理局（FDA）仅批准了三种用于治疗AUD的药物，所有这些药物的疗效都有限。由于转录因子和表观遗传修饰因子能够改变大量基因的表达，且这种改变通常具有高度的细胞类型和脑区特异性，因此它们有望成为开发针对慢性酒精滥用潜在神经回路的AUD治疗方法的新靶点。在本章中，我们将讨论那些可以作为药物靶点的转录调节因子，并且这些因子在作为靶点时已显示出在减少酒精摄入方面具有一定疗效。具体而言，我们将讨论转录因子环磷腺苷反应元件结合蛋白（CREB）、过氧化物酶体增殖物激活受体（PPARs）、活化B细胞核因子κB（NF-κB）和糖皮质激素受体（GR），以及表观遗传酶，即DNA甲基转移酶（DNMTs）和组蛋白脱乙酰酶（HDACs）。
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