Therapeutic Potential of a Prolyl Hydroxylase Inhibitor FG-4592 for Parkinson's Diseases in Vitro and in Vivo: Regulation of Redox Biology and Mitochondrial Function.
Therapeutic Potential of a Prolyl Hydroxylase Inhibitor FG-4592 for Parkinson's Diseases in Vitro and in Vivo: Regulation of Redox Biology and Mitochondrial Function.
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脯氨酰羟化酶抑制剂 FG-4592 对帕金森病的体外和体内治疗潜力：氧化还原生物学和线粒体功能的调节
DOI：
10.3389/fnagi.2018.00121
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发表时间：
2018
影响因子：
4.8
通讯作者：
Wu YC
中科院分区：
文献类型：
--
作者：
Li X;Cui XX;Chen YJ;Wu TT;Xu H;Yin H;Wu YC
缺氧诱导因子-1 α（Hypoxia-inducible factor-1α，HIF-1α）作为调节细胞缺氧反应的主要转录因子，在帕金森病（Parkinson 'sdisease，PD）的发病机制中起重要作用。HIF-1α通常在被脯氨酰羟化酶（PHD）羟基化后通过泛素化降解。新出现的证据表明，HIF PHD抑制剂（HIF-PHI）可能通过增加HIF-1α水平对PD具有神经保护作用。然而，由于缺乏适当的临床化合物和对潜在分子机制的理解，HIF-PHI对PD的治疗益处仍然探索不足。在这项研究中，我们检查了一种新的HIF-PHI FG-4592的治疗获益，该药物目前正在进行III期临床试验，用于治疗PD模型中慢性肾脏疾病（CKD）患者的贫血。FG-4592可减弱MPP+诱导的SH-SY 5 Y细胞凋亡和酪氨酸羟化酶（TH）丢失。FG-4592预处理可减轻MPP+诱导的线粒体膜电位（MMP）、线粒体耗氧率（OCR）、活性氧（ROS）和ATP产生的损失。此外，FG-4592通过上调核因子红细胞2 p45相关因子2（Nrf-2）、血红素加氧酶-1（HO-1）和超氧化物歧化酶2（SOD 2）来平衡氧化应激。FG-4592处理还通过增加AMP激活蛋白激酶（AMPK）的磷酸化诱导过氧化物酶体增殖物激活受体-γ共激活因子-1 α（PGC-1α）的表达。在MPTP处理的小鼠中，FG-4592可防止MPTP诱导的黑质TH阳性神经元丢失，并减轻行为障碍。总的来说，我们的研究表明，FG-4592通过改善氧化应激下的线粒体功能，是一种有前途的PD治疗策略。
As the main transcription factor that regulates the cellular responses to hypoxia, Hypoxia-inducible factor-1α (HIF-1α) plays an important role in the pathogenesis of Parkinson’s disease (PD). HIF-1α is normally degraded through ubiquitination after hydroxylation by prolyl hydroxylases (PHD). Emerging evidence has suggested that HIF PHD inhibitors (HIF-PHI) may have neuroprotective effects on PD through increasing HIF-1α levels. However, the therapeutic benefit of HIF-PHI for PD remains poorly explored due to the lack of proper clinical compounds and understanding of the underlying molecular mechanisms. In this study, we examined the therapeutic benefit of a new HIF-PHI, FG-4592, which is currently in phase 3 clinical trials to treat anemia in patients with chronic kidney diseases (CKD) in PD models. FG-4592 attenuates MPP+ -induced apoptosis and loss of tyrosine hydroxylase (TH) in SH-SY5Y cells. Pretreatment with FG-4592 mitigates MPP+-induced loss of mitochondrial membrane potential (MMP), mitochondrial oxygen consumption rate (OCR), production of reactive oxygen species (ROS) and ATP. Furthermore, FG-4592 counterbalances the oxidative stress through up-regulating nuclear factor erythroid 2 p45-related factor 2 (Nrf-2), heme oxygenase-1 (HO-1) and superoxide dismutase 2 (SOD2). FG-4592 treatment also induces the expression of Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) through increasing the phosphorylation of AMP-activated protein kinase (AMPK). In MPTP-treated mice, FG-4592 protects against MPTP-induced loss of TH-positive neurons of substantia nigra and attenuates behavioral impairments. Collectively, our study demonstrates that FG-4592 is a promising therapeutic strategy for PD through improving the mitochondrial function under oxidative stress.
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影响因子：
56.9
作者：
Jaakkola, P;Mole, DR;Ratcliffe, PJ
通讯作者：
Ratcliffe, PJ
影响因子：
13.6
作者：
Besarab, Anatole;Chernyayskaya, Elena;Neff, Thomas B.
通讯作者：
Neff, Thomas B.
影响因子：
5.1
作者：
Haavik, Jan;Toska, Karen
通讯作者：
Toska, Karen
影响因子：
4.8
作者：
Lee, Donna W.;Rajagopalan, Subramanian;Andersen, Julie K.
通讯作者：
Andersen, Julie K.
DOI：
10.1126/science.aam9080
发表时间：
2017-09-22
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Burbulla LF;Song P;Mazzulli JR;Zampese E;Wong YC;Jeon S;Santos DP;Blanz J;Obermaier CD;Strojny C;Savas JN;Kiskinis E;Zhuang X;Krüger R;Surmeier DJ;Krainc D
通讯作者：
Krainc D