Activation of HIF-1α and Nrf2 is a primary component of cellular response to oxidative stress, and activation of HIF-1α and Nrf2 provides neuroprotection in models of neurodegenerative disorders, including ischemic stroke, Alzheimer’s and Parkinson’s diseases. Screening a library of CNS-targeted drugs using novel reporters for HIF-1α and Nrf2 elevation in neuronal cells revealed histone deacetylase (HDAC) inhibitors as potential activators of these pathways. We report the identification of phenylhydroxamates as single agents exhibiting tripartite inhibition of HDAC6, inhibition of HIF-1 prolyl hydroxylase (PHD), and activation of Nrf2. Two superior tripartite agents, ING-6 and ING-66, showed neuroprotection against various cellular insults, associated with stabilization of both Nrf2 and HIF-1, and expression of their respective target genes in vitro and in vivo. Discovery of the innate ability of phenylhydroxamate HDAC inhibitors to activate Nrf2 and HIF provides a novel route to multifunctional neuroprotective agents and cautions against HDAC6 selective inhibitors as chemical probes of specific HDAC isoform function.

中文翻译：

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Nrf2的激活和低氧适应性反应有助于苯氧肟酸选择性HDAC6抑制剂引起的神经保护作用。

HIF-1α和Nrf2的激活是细胞对氧化应激反应的主要组成部分，HIF-1α和Nrf2的激活在神经变性疾病（包括缺血性中风，阿尔茨海默氏病和帕金森氏病）的模型中提供了神经保护作用。使用新型记者报道神经元细胞中HIF-1α和Nrf2升高，筛选以CNS为靶标的药物文库揭示了组蛋白脱乙酰基酶（HDAC）抑制剂是这些途径的潜在激活剂。我们报告鉴定苯氧肟酸酯作为展示HDAC6的三方抑制，抑制HIF-1脯氨酰羟化酶（PHD）和激活Nrf2的单一药物。两种优异的三方试剂ING-6和ING-66对多种细胞损伤均表现出神经保护作用，与Nrf2和HIF-1的稳定相关，和体内和体外各自靶基因的表达。苯氧肟酸酯HDAC抑制剂激活Nrf2和HIF的先天能力的发现为多功能神经保护剂提供了一条新途径，并警告不要将HDAC6选择性抑制剂用作特定HDAC同工型功能的化学探针。