Treating Depression with Histone Deacetylase Inhibitors

用组蛋白脱乙酰酶抑制剂治疗抑郁症

• 批准号: 6927476
• 负责人: Schahram Akbarian
• 金额: $ 24.06万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6927476
• 关键词: acetylation; amidohydrolases; angiogenesis factor; antidepressants; behavior test; biological signal transduction; blood brain barrier; chromatin immunoprecipitation; clinical depression; drug screening /evaluation; enzyme inhibitors; genetic promoter element; hippocampus; histones; laboratory mouse; learned helplessness; mental disorder chemotherapy; neurotrophic factors; nonhuman therapy evaluation; pharmacogenetics; pharmacokinetics; polymerase chain reaction; psychopharmacology

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.

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，美国成年人的终生患病率高达 16.2%。 20世纪50年代第一种药理学抗抑郁药物的推出，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，目前使用的所有抗抑郁药物都会调节单胺神经传递，需要六到八周才能发挥作用。尽管如此，难治性抑郁症通常是指对至少一项足够剂量和持续时间的抗抑郁药物试验反应不足，影响高达 50-60% 的患者。因此，有必要测试和开发具有新颖作用机制和更快速治疗反应的抗抑郁药。该申请的重点是临床前研究，以评估一类新型治疗药物——历史悠久的脱乙酰酶抑制剂 (HDACi) 的抗抑郁潜力。我们的中心目标是 1) 找出跨越血脑屏障的 HDACi 是否会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；2) 研究 HDACi 诱导的染色质重塑，包括近端组蛋白乙酰化参与神经营养蛋白和/或血管生成内皮信号传导途径的基因的启动子序列。行为实验（目标#1）以初步数据为指导，初步数据表明，与对照组相比，用 HDACi（丁酸钠）治疗 14-16 天的小鼠表现出较低水平的行为绝望。染色质研究（目标#2）将依赖于使用位点和修饰特异性抗组蛋白抗体对海马提取物进行免疫沉淀，结合近端启动子序列的定量实时 PCR 和 10 种神经营养和血管生成编码序列的 RT-PCR被认为在神经生物学或抑郁症治疗中发挥作用的因素。 预计这些新方法将为 HDACi 的抗抑郁潜力提供有希望的初步见解，并将海马染色质的表观遗传修饰确立为抑郁症神经生物学的重要分子机制。