SAHA enhances synaptic function and plasticity in vitro but has limited brain availability in vivo and does not impact cognition.
SAHA enhances synaptic function and plasticity in vitro but has limited brain availability in vivo and does not impact cognition.
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DOI：
10.1371/journal.pone.0069964
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Zhou Q
中科院分区：
文献类型：
--
作者：
Hanson JE;La H;Plise E;Chen YH;Ding X;Hanania T;Sabath EV;Alexandrov V;Brunner D;Leahy E;Steiner P;Liu L;Scearce-Levie K;Zhou Q
亚甲基苯胺羟肟酸（SAHA）是一种组蛋白去乙酰化酶（hdac）抑制剂，用于治疗皮肤T细胞淋巴瘤（CTCL），目前正在考虑用于其他适应症。体内研究表明，降低HDAC功能可以增强突触功能和记忆，这提高了SAHA治疗可能具有神经学益处的可能性。我们首先利用大鼠器官型海马脑切片在体外检测了SAHA对突触功能的影响。经过几天的SAHA治疗后，基底兴奋性突触功能增强，而非抑制性突触功能增强。突触前释放概率和神经元固有兴奋性未受影响，提示SAHA治疗选择性地增强了突触后兴奋功能。此外，SAHA处理后，兴奋性突触的长期增强（LTP）增强，而长期抑制（LTD）受损。尽管体外突触增强，但体内SAHA治疗并没有挽救阿尔茨海默病（AD） Tg2576小鼠模型的记忆缺陷。由于缺乏对行为的影响，药代动力学分析表明SAHA的脑可利用性较差。使用C57Bl6小鼠的高含量表型表征对体内SAHA治疗进行更广泛的评估，未能证明急性或慢性注射高达150 mg/kg的SAHA对行为有显著影响。SAHA被发现是血脑屏障（BBB）外排转运蛋白Pgp和Bcrp1的底物，这可能解释了低脑暴露和缺乏行为影响。因此，虽然我们的体外实验数据表明HDAC抑制可以增强兴奋性突触的强度和增强，但我们的体内实验数据表明，大脑可用性有限可能导致外周递送后SAHA缺乏行为影响。这些结果并不能预测SAHA在临床使用时对中枢神经系统的影响，也强调了在解释临床前行为药理学时分析脑药物水平的重要性。
Suberoylanilide hydroxamic acid (SAHA) is an inhibitor of histone deacetylases (HDACs) used for the treatment of cutaneous T cell lymphoma (CTCL) and under consideration for other indications. In vivo studies suggest reducing HDAC function can enhance synaptic function and memory, raising the possibility that SAHA treatment could have neurological benefits. We first examined the impacts of SAHA on synaptic function in vitro using rat organotypic hippocampal brain slices. Following several days of SAHA treatment, basal excitatory but not inhibitory synaptic function was enhanced. Presynaptic release probability and intrinsic neuronal excitability were unaffected suggesting SAHA treatment selectively enhanced postsynaptic excitatory function. In addition, long-term potentiation (LTP) of excitatory synapses was augmented, while long-term depression (LTD) was impaired in SAHA treated slices. Despite the in vitro synaptic enhancements, in vivo SAHA treatment did not rescue memory deficits in the Tg2576 mouse model of Alzheimer’s disease (AD). Along with the lack of behavioral impact, pharmacokinetic analysis indicated poor brain availability of SAHA. Broader assessment of in vivo SAHA treatment using high-content phenotypic characterization of C57Bl6 mice failed to demonstrate significant behavioral effects of up to 150 mg/kg SAHA following either acute or chronic injections. Potentially explaining the low brain exposure and lack of behavioral impacts, SAHA was found to be a substrate of the blood brain barrier (BBB) efflux transporters Pgp and Bcrp1. Thus while our in vitro data show that HDAC inhibition can enhance excitatory synaptic strength and potentiation, our in vivo data suggests limited brain availability may contribute to the lack of behavioral impact of SAHA following peripheral delivery. These results do not predict CNS effects of SAHA during clinical use and also emphasize the importance of analyzing brain drug levels when interpreting preclinical behavioral pharmacology.
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影响因子：
3.7
作者：
Beconi M;Aziz O;Matthews K;Moumné L;O'Connell C;Yates D;Clifton S;Pett H;Vann J;Crowley L;Haughan AF;Smith DL;Woodman B;Bates GP;Brookfield F;Bürli RW;McAllister G;Dominguez C;Munoz-Sanjuan I;Beaumont V
通讯作者：
Beaumont V
影响因子：
14.8
作者：
Bradner, James E.;West, Nathan;Grachan, Melissa L.;Greenberg, Edward F.;Haggarty, Stephen J.;Warnow, Tandy;Mazitschek, Ralph
通讯作者：
Mazitschek, Ralph
影响因子：
5.3
作者：
Comery, TA;Martone, RL;Marquis, KL
通讯作者：
Marquis, KL
影响因子：
5.3
作者：
Hanson, Jesse E.;Deng, Lunbin;Zhou, Qiang
通讯作者：
Zhou, Qiang
影响因子：
7.6
作者：
Kilgore, Mark;Miller, Courtney A.;Rumbaugh, Gavin
通讯作者：
Rumbaugh, Gavin