摘要
Oxidative stress has been implicated in the progression of a number of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis(ALS). These diseases are characterized by extensive oxidative damage to lipids, proteins and DNA. This damage can lead to cell death by a variety of different mechanisms, either by deactivating important processes or by upregulating toxic cascades. Oxidative stress is the result of an imbalance in the pro-oxidant/antioxidant homeostasis leading to the generation of toxic reactive oxygen species (ROS). ROS have a normal metabolic role in cell signalling and are generated by the interaction of oxygen with redox-active metal ions. As ROS can be damaging both metals and ROS are tightly regulated. Genetics has identified Aβ, α-synuclein and SOD as playing a pivotal role in AD, PD and ALS, respectively. These proteins are the major components of the deposits associated with these diseases. All these proteins have been shown to interact with redox-active metal ions with the subsequent generation of ROS. Aβ will coordinate copper and iron and generate H2O2 with the further generation of ROS through Fenton chemistry. α-synuclein regulates the uptake of vesicular dopamine, and a breakdown in this process allows the build-up of dopamine in the cytoplasm. Dopamine coordinates iron and induces the formation of ROS. Destabilization of the active site of SOD allows a corruption of this antioxidant enzyme such that it becomes pro-oxidant. Excitotoxicity is a downstream consequence of calcium dysregulation as a result of unregulated ROS. Drugs targeting this toxicity (Memantine in AD, Amantadine in PD and Riluzole in ALS) have modest clinical benefit. The antioxidant α-tocopherol has shown clinical promise against AD. Inhibiting metal-mediated redox processes has shown benefit in mouse models of AD and PD and encouraging promise in a small Phase II clinical trial for AD. AbstractOxidative stress has been implicated in the progression of Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Oxygen is vital for life but is also potentially dangerous, and a complex system of checks and balances exists for utilizing this essential element. Oxidative stress is the result of an imbalance in pro-oxidant/antioxidant homeostasis that leads to the generation of toxic reactive oxygen species. The systems in place to cope with the biochemistry of oxygen are complex, and many questions about the mechanisms of oxygen regulation remain unanswered. However, this same complexity provides a number of therapeutic targets, and different strategies, including novel metal–protein attenuating compounds, aimed at a variety of targets have shown promise in clinical studies.
摘要译文
氧化应激与许多神经退行性疾病的发展有关，包括阿尔茨海默氏病（AD），帕金森氏病（PD）和肌萎缩性侧索硬化症（ALS）。这些疾病的特征是对脂质，蛋白质和DNA的广泛氧化损伤。这种破坏可以通过各种不同的机制导致细胞死亡，或者通过失活重要过程或通过上调毒性级联反应而导致。氧化应激是促氧化剂/抗氧化剂体内稳态失衡的结果，导致有毒活性氧（ROS）的产生。 ROS在细胞信号传导中具有正常的代谢作用，是由氧气与氧化还原活性金属离子的相互作用产生的。由于ROS可能会破坏金属，因此ROS受到严格调节。遗传学已确定Aβ，α-突触核蛋白和SOD分别在AD，PD和ALS中起关键作用。这些蛋白质是与这些疾病有关的沉积物的主要成分。所有这些蛋白质已显示与氧化还原活性金属离子相互作用，并随后产生ROS。 Aβ将通过Fenton化学与铜和铁配位，并随着ROS的进一步生成而生成H 2 O 2。 α-突触核蛋白调节水泡多巴胺的摄取，而这一过程的破坏使多巴胺在细胞质中积累。多巴胺能协调铁并诱导ROS的形成。 SOD活性位点的不稳定会破坏该抗氧化酶，使其变成前氧化剂。兴奋性毒性是由于ROS失控导致钙失调的下游结果。针对这种毒性的药物（AD中的美金刚，PD中的金刚烷胺和ALS中的利鲁唑）具有适度的临床益处。抗氧化剂α-生育酚已显示出抗AD的临床前景。抑制金属介导的氧化还原过程已在AD和PD小鼠模型中显示出益处，并在一项小型的AD II期临床试验中令人鼓舞。摘要氧化应激与阿尔茨海默氏病，帕金森氏病和肌萎缩性侧索硬化症的发展有关。氧气对于生命至关重要，但同时也具有潜在的危险，因此存在利用此基本元素的复杂制衡体系。氧化应激是促氧化剂/抗氧化剂体内稳态失衡的结果，导致体内生成有毒的活性氧。应付氧气生物化学的系统很复杂，关于氧气调节机制的许多问题仍未得到解答。但是，这种相同的复杂性提供了许多治疗靶标，针对各种靶标的不同策略（包括新型金属-蛋白质减毒化合物）在临床研究中显示出了希望。
Kevin J. Barnham;Colin L. Masters;Ashley I. Bush. Neurodegenerative diseases and oxidative stress[J]. Nature Reviews Drug Discovery, 2004,3(3): 205-214