A selective HDAC 1/2 inhibitor modulates chromatin and gene expression in brain and alters mouse behavior in two mood-related tests.
A selective HDAC 1/2 inhibitor modulates chromatin and gene expression in brain and alters mouse behavior in two mood-related tests.
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DOI：
10.1371/journal.pone.0071323
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Petryshen TL
中科院分区：
文献类型：
--
作者：
Schroeder FA;Lewis MC;Fass DM;Wagner FF;Zhang YL;Hennig KM;Gale J;Zhao WN;Reis S;Barker DD;Berry-Scott E;Kim SW;Clore EL;Hooker JM;Holson EB;Haggarty SJ;Petryshen TL
精神疾病，包括精神分裂症、双相情感障碍和严重抑郁症，预计将在未来十年内成为全球疾病负担的主要来源。药物治疗是主要的治疗方法，尽管通常无效，但在过去50年中基本保持不变，突出了对新靶点发现和改进机制治疗的需求。在此，我们在野生型小鼠中检查了用化合物60（Cpd-60）（一种I类组蛋白脱乙酰酶（HDAC）家族成员HDAC 1和HDAC 2的缓慢结合的基于苯甲酰胺的抑制剂）在对临床有效药物有反应的情绪相关行为测定中的长期全身性治疗的影响。Cpd-60治疗一周与急性安非他明攻击后减弱的自发活动相关。此外，经处理的小鼠在强迫游泳测试中表现出减少的不动性。这些变化分别与临床情绪稳定剂和抗抑郁药的既定作用一致。从用Cpd-60处理的小鼠的特定脑区域（前额叶皮质、丘脑核、海马）的全基因组表达谱确定了基因表达变化，包括与先前在锂处理的小鼠中报道的那些显著重叠的转录物的一小部分。脑中的HDAC抑制通过组蛋白乙酰化的增加而得到证实，所述组蛋白乙酰化在整体上以及使用染色质免疫沉淀在上调的转录物的启动子区域处均增加，这一发现与HDAC靶标的体内接合一致。相比之下，辛二酰苯胺异羟肟酸（SAHA），一种非选择性的快速结合，异羟肟酸HDAC 1/2/3/6抑制剂，足以增加脑中的组蛋白乙酰化，但不改变情绪相关的行为，并具有不同的转录调控作用相比，化合物60。这些结果提供的证据表明，大脑中HDAC 1和HDAC 2的选择性抑制可以提供基于表观遗传学的靶点，用于开发改善的治疗方法，用于治疗情绪障碍和其他具有改变的染色质介导的神经可塑性的大脑疾病。
Psychiatric diseases, including schizophrenia, bipolar disorder and major depression, are projected to lead global disease burden within the next decade. Pharmacotherapy, the primary – albeit often ineffective – treatment method, has remained largely unchanged over the past 50 years, highlighting the need for novel target discovery and improved mechanism-based treatments. Here, we examined in wild type mice the impact of chronic, systemic treatment with Compound 60 (Cpd-60), a slow-binding, benzamide-based inhibitor of the class I histone deacetylase (HDAC) family members, HDAC1 and HDAC2, in mood-related behavioral assays responsive to clinically effective drugs. Cpd-60 treatment for one week was associated with attenuated locomotor activity following acute amphetamine challenge. Further, treated mice demonstrated decreased immobility in the forced swim test. These changes are consistent with established effects of clinical mood stabilizers and antidepressants, respectively. Whole-genome expression profiling of specific brain regions (prefrontal cortex, nucleus accumbens, hippocampus) from mice treated with Cpd-60 identified gene expression changes, including a small subset of transcripts that significantly overlapped those previously reported in lithium-treated mice. HDAC inhibition in brain was confirmed by increased histone acetylation both globally and, using chromatin immunoprecipitation, at the promoter regions of upregulated transcripts, a finding consistent with in vivo engagement of HDAC targets. In contrast, treatment with suberoylanilide hydroxamic acid (SAHA), a non-selective fast-binding, hydroxamic acid HDAC 1/2/3/6 inhibitor, was sufficient to increase histone acetylation in brain, but did not alter mood-related behaviors and had dissimilar transcriptional regulatory effects compared to Cpd-60. These results provide evidence that selective inhibition of HDAC1 and HDAC2 in brain may provide an epigenetic-based target for developing improved treatments for mood disorders and other brain disorders with altered chromatin-mediated neuroplasticity.
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DOI：
10.1523/jneurosci.1758-09.2009
发表时间：
2009-09-16
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Covington HE 3rd;Maze I;LaPlant QC;Vialou VF;Ohnishi YN;Berton O;Fass DM;Renthal W;Rush AJ 3rd;Wu EY;Ghose S;Krishnan V;Russo SJ;Tamminga C;Haggarty SJ;Nestler EJ
通讯作者：
Nestler EJ
影响因子：
5
作者：
Hooker, Jacob M.;Kim, Sung Won;Alexoff, David;Xu, Youwen;Shea, Colleen;Reid, Alicia;Volkow, Nora;Fowler, Joanna S.
通讯作者：
Fowler, Joanna S.
影响因子：
3.3
作者：
Hodes, G. E.;Brookshire, B. R.;Hill-Smith, T. E.;Teegarden, S. L.;Berton, O.;Lucki, I.
通讯作者：
Lucki, I.
影响因子：
3.9
作者：
Fang, HL;Shenoy, S;Runge-Morris, M
通讯作者：
Runge-Morris, M
影响因子：
5.3
作者：
Baltan, Selva;Murphy, Sean P.;Morrison, Richard S.
通讯作者：
Morrison, Richard S.