LBH589, A Hydroxamic Acid-Derived HDAC Inhibitor, is Neuroprotective in Mouse Models of Huntington's Disease.
LBH589, A Hydroxamic Acid-Derived HDAC Inhibitor, is Neuroprotective in Mouse Models of Huntington's Disease.
复制标题
DOI：
10.3233/jhd-160226
复制
发表时间：
2016-12-15
期刊：
影响因子：
--
通讯作者：
Hersch S
中科院分区：
文献类型：
--
作者：
Chopra V;Quinti L;Khanna P;Paganetti P;Kuhn R;Young AB;Kazantsev AG;Hersch S
背景资料：HDAC抑制剂对基因转录的调节已反复显示在亨廷顿病（HD）的细胞、无脊椎动物和啮齿动物模型中具有神经保护作用。然而，很难将这些治疗方法转化为临床，因为现有的化合物具有有限的效力或大脑生物利用度。目的：在本研究中，我们评估了LBH 589（一种口服生物可利用的异羟肟酸衍生的非选择性HDAC抑制剂）在HD小鼠模型中的治疗潜力。方法：使用各种生化、行为和神经病理学结果测量在两种HD小鼠模型中测试LBH 589的功效。结果如下：我们表明，LBH 589穿过血脑屏障，诱导组蛋白超乙酰化，并防止纹状体神经元萎缩R6/2 HD小鼠。在全长基因敲入HD小鼠中，LBH 589治疗改善了运动表现并减少了神经元萎缩。结论：我们在HD的片段和全长小鼠模型中LBH 589的有效结果表明，LBH 589是HD患者临床评估的有希望的候选物，并证实非选择性HDAC抑制剂可以是可行的临床候选物。
Background: Modulation of gene transcription by HDAC inhibitors has been shown repeatedly to be neuroprotective in cellular, invertebrate, and rodent models of Huntington’s disease (HD). It has been difficult to translate these treatments to the clinic, however, because existing compounds have limited potency or brain bioavailability. Objective: In the present study, we assessed the therapeutic potential of LBH589, an orally bioavailable hydroxamic acid-derived nonselective HDAC inhibitor in mouse models of HD. Method: The efficacy of LBH589 is tested in two HD mouse models using various biochemical, behavioral and neuropathological outcome measures. Results: We show that LBH589 crosses the blood brain barrier; induces histone hyperacetylation and prevents striatal neuronal shrinkage in R6/2 HD mice. In full-length knock-in HD mice LBH589-treatment improves motor performance and reduces neuronal atrophy. Conclusions: Our efficacious results of LBH589 in fragment and full-length mouse models of HD suggest that LBH589 is a promising candidate for clinical assessment in HD patients and provides confirmation that non-selective HDAC inhibitors can be viable clinical candidates.