Neuropharmacology Section, Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
Trends Pharmacol Sci. 2012 Jun;33(6):295-303. doi: 10.1016/j.tips.2012.03.008. Epub 2012 Apr 11.
Oxidative stress is a key pathologic factor in neurodegenerative diseases such as Alzheimer and Parkinson diseases (AD, PD). The failure of free-radical-scavenging antioxidants in clinical trials pinpoints an urgent need to identify and to block major sources of oxidative stress in neurodegenerative diseases. As a major superoxide-producing enzyme complex in activated phagocytes, phagocyte NADPH oxidase (PHOX) is essential for host defense. However, recent preclinical evidence has underscored a pivotal role of overactivated PHOX in chronic neuroinflammation and progressive neurodegeneration. Deficiency in PHOX subunits mitigates neuronal damage induced by diverse insults/stresses relevant to neurodegenerative diseases. More importantly, suppression of PHOX activity correlates with reduced neuronal impairment in models of neurodegenerative diseases. The discovery of PHOX and non-phagocyte NADPH oxidases in astroglia and neurons further reinforces the crucial role of NADPH oxidases in oxidative stress-mediated chronic neurodegeneration. Thus, proper modulation of NADPH oxidase activity might hold therapeutic potential for currently incurable neurodegenerative diseases.
氧化应激是阿尔茨海默病和帕金森病等神经退行性疾病的关键病理因素。临床试验中自由基清除抗氧化剂的失败，凸显出迫切需要识别和阻断神经退行性疾病中主要的氧化应激源。作为激活吞噬细胞中主要的超氧化物产生酶复合物，吞噬细胞 NADPH 氧化酶（PHOX）对宿主防御至关重要。然而，最近的临床前证据强调了过度激活的 PHOX 在慢性神经炎症和进行性神经退行性变中的关键作用。PHOX 亚基的缺乏减轻了与神经退行性疾病相关的多种损伤/应激诱导的神经元损伤。更重要的是，在神经退行性疾病模型中，PHOX 活性的抑制与神经元损伤的减少相关。星形胶质细胞和神经元中 PHOX 和非吞噬细胞 NADPH 氧化酶的发现进一步证实了 NADPH 氧化酶在氧化应激介导的慢性神经退行性变中的关键作用。因此，适当调节 NADPH 氧化酶的活性可能为目前无法治愈的神经退行性疾病提供治疗潜力。
