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，在美国成年人中终生患病率高达16.2%。20世纪50年代首次引入抗抑郁药物，以及随后开发的副作用较低的药物，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是调节单胺类神经传递，需要6到8周才能发挥作用。然而，治疗难治性抑郁症（通常指对至少一种剂量和持续时间足够的抗抑郁药物试验反应不足）影响了多达50-60%的患者。因此，有必要测试和开发具有概念上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的抗抑郁潜力，历史性去乙酰化酶抑制剂（HDACi）。我们的主要目标是：1)发现HDACi穿过血脑屏障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，包括组蛋白乙酰化，以及参与神经营养因子和/或血管生成-内皮信号通路的基因近端启动子序列。行为实验（目标1）是由初步数据指导的，这些数据表明，与对照组相比，使用HDACi（丁酸钠）治疗14-16天的小鼠表现出较低的行为绝望水平。染色质研究（Aim #2）将依赖于海马提取物的免疫沉淀和位点特异性和修饰特异性抗组蛋白抗体，结合定量实时PCR检测近端启动子序列和RT-PCR检测10种神经营养和血管生成因子的编码序列，这些因子被认为在神经生物学或抑郁症治疗中发挥作用。

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.