Treating Depression with Histone Deacetylase Inhibitors

描述（由申请人提供）：抑郁症被认为是当今社会最严重的疾病之一，在美国成年人口中终身患病率高达16.2%。在20世纪50年代，第一种抗抑郁药物的引入，以及随后副作用较低的药物的开发，极大地改善了抑郁症患者的治疗前景。值得注意的是，现在使用的所有抗抑郁药物都能调节单胺神经传递，并需要6到8周才能发挥作用。尽管如此，难治性抑郁症，通常是指对至少一种适当剂量和持续时间的抗抑郁药试验反应不足，影响高达50-60%的患者。因此，有必要测试和开发具有概念新颖的作用机制和更快速的治疗反应的抗抑郁药。本申请的重点是临床前研究，以评估一类新型治疗药物，历史性脱乙酰酶抑制剂（HDACi）的抗抑郁潜力。我们的中心目标是1）发现穿过血脑屏障的HDACi是否改变啮齿动物模型中焦虑、行为绝望和习得性无助的测试表现，以及2）研究HDACi诱导的染色质重塑，包括在参与神经营养因子和/或血管生成内皮信号传导途径的基因的近端启动子序列处的组蛋白乙酰化。行为实验（目标#1）由初步数据指导，初步数据表明与对照相比，用HDACi、丁酸钠处理14-16天的小鼠显示出较低水平的行为绝望。染色质研究（目标#2）将依赖于海马提取物与位点特异性和修饰特异性抗组蛋白抗体的免疫沉淀，结合近端启动子序列的定量真实的时间PCR和10种神经营养因子和血管生成因子的编码序列的RT-PCR，这些因子被认为在神经生物学或抑郁症治疗中发挥作用。 预计这些新的方法将提供有希望的第一次深入了解HDACi的抗抑郁潜力，并将建立海马染色质的表观遗传修饰作为抑郁症的神经生物学的重要分子机制。

DESCRIPTION (provided by applicant): Depression is considered one of the most serious disorders in today's society, with a lifetime prevalence as high as 16.2% in the US adult population. The introduction of the first pharmacological antidepressant medications in the 1950s, and subsequent development of drugs with lower side-effect profiles has greatly improved the therapeutic outlook for depressed patients. Notably, all the antidepressant drugs now in use modulate monoamine neurotransmission and take six to eight weeks to exert their effects. Still, treatment-resistant depression, which typically refers to inadequate response to at least one antidepressant trial of adequate dose and duration, affects up to 50-60% of patients. Therefore, it will be necessary to test and develop antidepressants with conceptually novel mechanisms of actions and a more rapid therapeutic response. The focus of this application is on pre-clinical studies to assess the antidepressant potential of a novel class of therapeutic drugs, historic deacetylase inhibitors (HDACi). Our central goals are to 1) find out if HDACi's that cross the blood-brain barrier alter test performance in rodent models for anxiety, behavioral despair and learned helplessness and 2) to study HDACi-induced chromatin-remodeling, including histone acetylation, at proximal promoter sequences of genes that are involved in neurotrophin and/or angiogenic-endothelial signaling pathways. The behavioral experiments (Aim #1) are guided by preliminary data demonstrating that mice treated for 14-16 days with the HDACi, sodium butyrate, show lower levels of behavioral despair, in comparison to controls. The chromatin studies (Aim #2) will rely on immunoprecipitation of hippocampal extracts with site- and modification-specific anti-histone antibodies, in conjunction with quantitative real time PCR for proximal promoter sequences and RT-PCR for coding sequences of 10 neurotrophic and angiogenic factors that are thought to play a role in the neurobiology or treatment of depression. It is expected that these novel approaches will provide promising first insights into the antidepressant potential of HDACi's and will establish the epigenetic modification of hippocampal chromatin as an important molecular mechanism for the neurobiology of depression.