Class I Histone Deacetylase Inhibition by Tianeptinaline Modulates Neuroplasticity and Enhances Memory.,ACS Chemical Neuroscience

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Class I Histone Deacetylase Inhibition by Tianeptinaline Modulates Neuroplasticity and Enhances Memory.
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2018-06-22 , DOI: 10.1021/acschemneuro.8b00116
Wen-Ning Zhao _{1,

2} , Balaram Ghosh _{1,

2} , Marshall Tyler _{1,

2} , Jasmin Lalonde _{1,

2} , Nadine F Joseph ₃ , Nina Kosaric _{1,

2} , Daniel M Fass _{1,

2} , Li-Huei Tsai ₃ , Ralph Mazitschek ₄ , Stephen J Haggarty _{1,

2}

Affiliation

Through epigenetic and other regulatory functions, the histone deacetylase (HDAC) family of enzymes has emerged as a promising therapeutic target for central nervous system and other disorders. Here we report on the synthesis and functional characterization of new HDAC inhibitors based structurally on tianeptine, a drug used primarily to treat major depressive disorder (MDD) that has a poorly understood mechanism of action. Since the chemical structure of tianeptine resembles certain HDAC inhibitors, we profiled the in vitro HDAC inhibitory activity of tianeptine and demonstrated its ability to inhibit the lysine deacetylase activity of a subset of class I HDACs. Consistent with a model of active site Zn2+ chelation by the carboxylic acid present in tianeptine, newly synthesized analogues containing either a hydroxamic acid or ortho-aminoanilide exhibited increased potency and selectivity among the HDAC family. This in vitro potency translated to improved efficacy in a panel of high-content imaging assays designed to assess HDAC target engagement and functional effects on critical pathways involved in neuroplasticity in both primary mouse neurons and, for the first time, human neurons differentiated from pluripotent stem cells. Most notably, tianeptinaline, a class I HDAC-selective analogue of tianeptine, but not tianeptine itself, increased histone acetylation, and enhanced CREB-mediated transcription and the expression of Arc (activity-regulated cytoskeleton-associated protein). Systemic in vivo administration of tianeptinaline to mice confirmed its brain penetration and was found to enhance contextual fear conditioning, a behavioral test of hippocampal-dependent memory. Tianeptinaline and its derivatives provide new pharmacological tools to dissect chromatin-mediated neuroplasticity underlying memory and other epigenetically related processes implicated in health and disease.

中文翻译：

Tianeptinaline对I类组蛋白去乙酰化酶的抑制作用可调节神经可塑性并增强记忆力。

通过表观遗传和其他调节功能，组蛋白脱乙酰基酶（HDAC）家族已成为中枢神经系统和其他疾病的有希望的治疗靶标。在这里，我们基于新肽的结构报道新的HDAC抑制剂的合成和功能表征，该肽主要用于治疗主要的抑郁症（MDD），其作用机理尚不清楚。由于替丁汀的化学结构类似于某些HDAC抑制剂，因此我们分析了替丁汀的体外HDAC抑制活性，并证明了其抑制I类HDAC子集的赖氨酸脱乙酰酶活性的能力。与天肽中存在的羧酸对活性位点Zn2 +螯合的模型相一致，在HDAC家族中，新合成的含有异羟肟酸或邻氨基苯胺的类似物表现出更高的效价和选择性。这种体外效能在一组旨在评估HDAC靶点参与和对小鼠原代神经元以及首次从多能干分化出的人类神经元的神经可塑性中的关键途径的功能性通路上评估HDAC目标参与和功能作用的高含量成像分析中，提高了疗效。细胞。最显着的是，田纳西林（一种田纳西汀的I类HDAC选择性类似物，但不是田纳西汀本身）增加了组蛋白乙酰化作用，并增强了CREB介导的转录和Arc（活性调节的细胞骨架相关蛋白）的表达。对小鼠进行全身体内的替丁汀林体内给药证实了它的大脑渗透能力，并发现它可以增强情境恐惧调节，这是对海马依赖性记忆的一项行为测试。Tianeptinaline及其衍生物提供了新的药理学工具，可以剖析染色质介导的神经可塑性，这些是记忆力和与健康和疾病有关的其他表观遗传学相关过程的基础。

更新日期：2018-06-22

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