Antioxidants in central nervous system diseases: preclinical promise and translational challenges.
Antioxidants in central nervous system diseases: preclinical promise and translational challenges.
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DOI：
10.3233/jad-2008-15314
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发表时间：
2008-11
期刊：
影响因子：
--
通讯作者：
Hensley K
中科院分区：
文献类型：
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作者：
Kamat CD;Gadal S;Mhatre M;Williamson KS;Pye QN;Hensley K
氧化损伤强烈地涉及神经变性疾病的发病机制，所述神经变性疾病包括阿尔茨海默病、肌萎缩性侧索硬化、亨廷顿病、帕金森病和中风（脑缺血/再灌注损伤）。这些疾病的转基因和毒素诱导模型的可用性促进了推定的抗氧化剂的临床前评价，从原型天然抗氧化剂如维生素E（α-生育酚）到复杂的合成自由基捕获剂和催化氧化剂。文献综述表明，抗氧化剂疗法在不同动物模型的临床前研究中取得了普遍成功，但在人类干预研究或临床试验中几乎没有益处。最近，维生素E在帕金森病中的试验和硝酮在中风中的治疗备受瞩目的失败，降低了在临床上追求抗氧化神经保护剂的热情。抗氧化剂的转化失望可能是由多种因素的组合引起的，包括未能理解候选药物与人类疾病的作用机制，以及未能使用与临床环境相关的浓度和时间参数进行临床前研究。这篇综述讨论了使用抗氧化剂预防或减轻人类神经疾病的基本原理，并对未来的临床前研究进行了调整，以提供更多的预测价值，选择药物转化为人体试验。
Oxidative damage is strongly implicated in the pathogenesis of neurodegenerative diseases including Alzheimer’s disease, amyotrophic lateral sclerosis, Huntington’s disease, Parkinson’s disease and stroke (brain ischemia/reperfusion injury). The availability of transgenic and toxin-inducible models of these conditions has facilitated the preclinical evaluation of putative antioxidant agents ranging from prototypic natural antioxidants such as vitamin E (α-tocopherol) to sophisticated synthetic free radical traps and catalytic oxidants. Literature review shows that antioxidant therapies have enjoyed general success in preclinical studies across disparate animal models, but little benefit in human intervention studies or clinical trials. Recent high-profile failures of vitamin E trials in Parkinson’s disease, and nitrone therapies in stroke, have diminished enthusiasm to pursue antioxidant neuroprotectants in the clinic. The translational disappointment of antioxidants likely arises from a combination of factors including failure to understand the drug candidate’s mechanism of action in relationship to human disease, and failure to conduct preclinical studies using concentration and time parameters relevant to the clinical setting. This review discusses the rationale for using antioxidants in the prophylaxis or mitigation of human neurodiseases, with a critical discussion regarding ways in which future preclinical studies may be adjusted to offer more predictive value in selecting agents for translation into human trials.