Antioxidants, oxidative stress, and degenerative neurological disorders
Antioxidants, oxidative stress, and degenerative neurological disorders
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DOI：
10.1046/j.1525-1373.1999.d01-140.x
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发表时间：
1999-12-01
影响因子：
--
通讯作者：
Floyd, RA
中科院分区：
文献类型：
--
作者：
Floyd, RA
最近，几种神经退行性疾病的临床试验越来越多地针对各种抗氧化剂的有效性进行评估。到目前为止，结果是令人鼓舞的，但可变的，因此令人困惑，抗氧化剂在几种退行性疾病中可能的临床有效性的理论基础已经出现在多年的基础科学中，普遍表明活性氧物种(ROS)和氧化损伤是涉及的过程中的重要因素。衰老是退行性神经系统疾病最重要的危险因素之一，我们实验室的基础科学工作主要集中在探索ROS和氧化应激在神经退行性过程中的作用。本综述汇集了我们在过去20年中通过遵循这一方法所学到的一些基本概念，特别是我们通过跟踪我们的偶然发现而获得的结果，即基于硝酮的自由基陷阱，α-苯基-叔丁基硝酮(PBN)，在几个实验性的神经退行性变模型中具有神经保护活性。PEN神经保护活性的机制基础本身似乎并不依赖于其一般的自由基捕获或抗氧化活性，但其在介导由促炎细胞因子和其他与增强的神经炎症过程、神经炎症过程相关的介质诱导的基因抑制方面的活性，部分由促炎细胞因子诱导，产生增加的ROS和反应性一氧化氮物种(RNS)以及其他具有神经毒性性质的未知成分，RNS的神经毒力量是由诱导型一氧化氮合酶(INOS)的活性形成的，与年龄匹配的对照组相比，阿尔茨海默病大脑受影响区域中3-硝基酪氨酸的形成增强。强化了神经炎症过程的重要性。INOS诱导涉及MAP激酶p38的磷酸化激活并可被IL-1β或过氧化氢诱导在培养的星形胶质细胞中，PEN和N-乙酰半胱氨酸抑制p38激活的作用在培养的星形胶质细胞中得到证实，激活的p38在阿尔茨海默病大脑受影响区域的淀粉样斑块周围的神经元中的展示证明在这种神经退行性疾病中信号转导过程增强，与神经炎症过程相关的ROS和RNS形成的主要主题以及抗氧化剂和PEN对这些过程的抑制继续为新的治疗方法带来有希望的指导，随着对相关基本过程的更多了解的积累，关于抗氧化剂的临床试验的结果将变得不那么令人困惑。
Recently, clinical trials of several neurodegenerative diseases have increasingly targeted the evaluation of the effectiveness of various antioxidants. The results so far are encouraging but variable and thus confusing, Rationale for the possible clinical effectiveness of antioxidants in several degenerative conditions has arisen out of the many years of basic science generally showing that reactive oxygen species (ROS) and oxidative damage are important factors in the processes involved. Aging is one of the most significant risk factors for degenerative neurological disorders, Basic science efforts in our laboratory have centered on exploring the role of ROS and oxidative stress in neurodegenerative processes. The present review brings together some of the basic concepts we have learned by following this approach for the last 20 years and specifically the results we have obtained by following up on our serendipitous findings that a nitrone-based free radical trap, alpha-phenyl-tert-butylnitrone (PBN), has neuroprotective activity in several experimental neurodegenerative models. The mechanistic basis of the neuroprotective activity of PEN does not appear to rely on its general free radical trapping or antioxidant activity per se, but its activity in mediating the suppression of genes induced by pro-inflammatory cytokines and other mediators associated with enhanced neuroinflammatory processes, Neuroinflammatory processes, induced in part by pro-inflammatory cytokines, yield enhanced ROS and reactive nitric oxide species (RNS) as well as other unknown components that have neurotoxic properties, Neurotoxic amounts of RNS are formed by the activity of inducible nitric oxide synthase (iNOS), The demonstration of enhanced 3-nitro-tyrosine formation in affected regions of the Alzheimer's brain, in comparison to age-matched controls, reinforces the importance of neuroinflammatory processes. iNOS induction involves activation by phosphorylation of the MAP kinase p38 and can be induced in cultured astrocytes by IL-1 beta or H2O2, The action of PEN and N-acetyl cysteine to suppress the activation of p38 was demonstrated in cultured astrocytes, The demonstration of activated p38 in neurons surrounding amyloid plaques in affected regions of the Alzheimer's brain attest to enhanced signal transduction processes in this neurodegenerative condition, The major themes of ROS and RNS formation associated with neuroinflammation processes and the suppression of these processes by antioxidants and PEN continue to yield promising leads for new therapies, Outcomes of clinical trials on antioxidants will become less confusing as more knowledge is amassed on the basic processes involved.