Eve Topf Centers of Excellence for Neurodegenerative Diseases Research and Department of Pharmacology, Rappaport Family Research Institute, Technion-Faculty of Medicine, Haifa, Israel.
Antioxid Redox Signal. 2010 Sep 15;13(6):919-49. doi: 10.1089/ars.2009.2929.
Accumulating evidence suggests that many cytotoxic signals occurring in the neurodegenerative brain can initiate neuronal death processes, including oxidative stress, inflammation, and accumulation of iron at the sites of the neuronal deterioration. Neuroprotection by iron chelators has been widely recognized with respect to their ability to prevent hydroxyl radical formation in the Fenton reaction by sequestering redox-active iron. An additional neuroprotective mechanism of iron chelators is associated with their ability to upregulate or stabilize the transcriptional activator, hypoxia-inducible factor-1alpha (HIF-1alpha). HIF-1alpha stability within the cells is under the control of a class of iron-dependent and oxygen-sensor enzymes, HIF prolyl-4-hydroxylases (PHDs) that target HIF-1alpha for degradation. Thus, an emerging novel target for neuroprotection is associated with the HIF system to promote stabilization of HIF-1alpha and increase transcription of HIF-1-related survival genes, which have been reported to be regulated in patient's brains afflicted with diverse neurodegenerative diseases. In accordance, a new potential therapeutic strategy for neurodegenerative diseases is explored, by which iron chelators would inhibit PHDs, target the HIF-1-signaling pathway and ultimately activate HIF-1-dependent neuroprotective genes. This review discusses two interrelated approaches concerning therapy targets in neurodegeneration, sharing in common the implementation of iron chelation activity: antioxidation and HIF-1-pathway activation.
越来越多的证据表明，神经退行性脑内发生的许多细胞毒性信号可以启动神经元死亡过程，包括氧化应激、炎症和神经元退化部位铁的积累。铁螯合剂的神经保护作用已得到广泛认可，因为它们能够通过螯合 Fenton 反应中的氧化还原活性铁来防止羟基自由基的形成。铁螯合剂的另一种神经保护机制与它们上调或稳定转录激活因子缺氧诱导因子-1α（HIF-1α）的能力有关。细胞内 HIF-1α的稳定性受一类铁依赖性和氧传感器酶（HIF 脯氨酰-4-羟化酶（PHD））的控制，这些酶将 HIF-1α作为降解的靶标。因此，与 HIF 系统相关的新的神经保护靶标与促进 HIF-1α稳定和增加 HIF-1 相关生存基因转录有关，据报道，这些基因在患有各种神经退行性疾病的患者大脑中受到调节。因此，探索了一种针对神经退行性疾病的新的潜在治疗策略，即铁螯合剂抑制 PHDs，靶向 HIF-1 信号通路，最终激活 HIF-1 依赖性神经保护基因。本文讨论了两种与神经变性治疗靶点相关的相互关联的方法，它们都具有相同的铁螯合活性：抗氧化和 HIF-1 通路激活。
