Department of Neuroscience, Genentech, Inc South San Francisco, California, United States of America.
PLoS One. 2013 Jul 26;8(7):e69964. doi: 10.1371/journal.pone.0069964. Print 2013.
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.
琥珀酰亚胺基戊二酰胺（SAHA）是组蛋白去乙酰化酶（HDAC）的抑制剂，用于治疗皮肤 T 细胞淋巴瘤（CTCL），并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，这增加了 SAHA 治疗可能具有神经益处的可能性。我们首先在大鼠器官型海马脑片上研究了 SAHA 对突触功能的体外影响。经过几天的 SAHA 处理后，基础兴奋性但非抑制性突触功能增强。突触前释放概率和固有神经元兴奋性不受影响，表明 SAHA 处理选择性增强了突触后兴奋性功能。此外，兴奋性突触的长时程增强（LTP）增强，而 SAHA 处理的切片中的长时程抑制（LTD）受损。尽管体外突触增强，但体内 SAHA 治疗不能挽救阿尔茨海默病（AD）Tg2576 小鼠模型的记忆缺陷。与缺乏行为影响一起，药代动力学分析表明 SAHA 的脑内可用性差。使用 C57Bl6 小鼠的高内涵表型特征更广泛地评估体内 SAHA 治疗，未能证明在急性或慢性注射后高达 150mg/kg SAHA 有明显的行为影响。可能解释了低脑暴露和缺乏行为影响的原因，SAHA 是血脑屏障（BBB）外排转运蛋白 Pgp 和 Bcrp1 的底物。因此，尽管我们的体外数据表明 HDAC 抑制可以增强兴奋性突触强度和增强作用，但我们的体内数据表明，脑内可用性有限可能导致外周给药后 SAHA 缺乏行为影响。这些结果并不能预测 SAHA 在临床使用期间对中枢神经系统的影响，也强调了当解释临床前行为药理学时分析脑内药物水平的重要性。
