HIF Prolyl Hydroxylase Inhibitors Prevent Neuronal Death Induced by Mitochondrial Toxins: Therapeutic Implications for Huntington's Disease and Alzheimer's Disease
HIF Prolyl Hydroxylase Inhibitors Prevent Neuronal Death Induced by Mitochondrial Toxins: Therapeutic Implications for Huntington's Disease and Alzheimer's Disease
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DOI：
10.1089/ars.2009.2800
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发表时间：
2010-02-01
影响因子：
6.6
通讯作者：
Ratan, Rajiv R.
中科院分区：
文献类型：
--
作者：
Niatsetskaya, Zoya;Basso, Manuela;Ratan, Rajiv R.
线粒体功能障碍是许多急性和慢性神经退行性疾病的中心特征，但临床批准的治疗干预措施才刚刚出现。在这里，我们展示了低氧诱导因子Pro-4-羟基酶(HIF PhDS)的低分子量抑制剂在防止线粒体毒素诱导的小鼠纹状体神经元细胞死亡方面的潜在临床应用，这些细胞表达“敲门”突变的Huntingtin等位基因。通过抑制HIF PHD对3-硝基丙酸(3-NP，一种复合II类抑制剂)诱导的毒性的保护作用，不需要挽救琥珀酸脱氢酶的活性。虽然突变的Huntingtin可以显著地诱导HIF-1αmRNA的表达，但短干扰RNA(SiRNA)耗尽HIF-1α并不影响这些细胞的稳态活性或对HIF PhD抑制剂诱导的3-NP诱导的死亡的保护作用。此外，3-NP诱导的复合体II对对照或突变纹状体神经元的抑制不会导致依赖于HIF的转录的激活。抑制HIF PHD也能保护大脑皮层神经元免受3-NP诱导的细胞毒性。抑制HIF-PHD对皮质神经元的保护作用与增强的血管内皮生长因子相关，但与PGC-1α基因的表达无关。综上所述，这些发现表明，HIF PhD抑制剂有望预防亨廷顿病和阿尔茨海默病等与中枢神经系统代谢应激相关的疾病中的细胞死亡。抗氧化剂。氧化还原信号。12435-443。
Mitochondrial dysfunction is a central feature of a number of acute and chronic neurodegenerative conditions, but clinically approved therapeutic interventions are only just emerging. Here we demonstrate the potential clinical utility of low molecular weight inhibitors of the hypoxia inducible factor prolyl-4-hydroxylases (HIF PHDs) in preventing mitochondrial toxin-induced cell death in mouse striatal neurons that express a "knock-in'' mutant Huntingtin allele. Protection from 3-nitropropionic acid (3-NP, a complex II inhibitor)-induced toxicity by HIF PHD inhibition occurs without rescue of succinate dehydrogenase activity. Although HIF-1 alpha mRNA is dramatically induced by mutant huntingtin, HIF-1 alpha depletion by short interfering RNAs (siRNA) does not affect steady-state viability or protection from 3-NP-induced death by HIF PHD inhibitors in these cells. Moreover, 3-NP-induced complex II inhibition in control or mutant striatal neurons does not lead to activation of HIF-dependent transcription. HIF PHD inhibition also protects cortical neurons from 3-NP-induced cytotoxicity. Protection of cortical neurons by HIF PHD inhibition correlates with enhanced VEGF but not PGC-1 alpha gene expression. Together, these findings suggest that HIF PHD inhibitors are promising candidates for preventing cell death in conditions such as Huntington's disease and Alzheimer's disease that are associated with metabolic stress in the central nervous system. Antioxid. Redox Signal. 12, 435-443.