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首页> 外文期刊>Drugs and aging >The role of iron in neurodegeneration: prospects for pharmacotherapy of Parkinson's disease.
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The role of iron in neurodegeneration: prospects for pharmacotherapy of Parkinson's disease.

机译：铁在神经变性中的作用：帕金森病的药物治疗前景。

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Although the aetiology of Parkinson's disease (PD) and related neurodegenerative disorders is still unknown, recent evidence from human and experimental animal models suggests that a misregulation of iron metabolism, iron-induced oxidative stress and free radical formation are major pathogenic factors. These factors trigger a cascade of deleterious events leading to neuronal death and the ensuing biochemical disturbances of clinical relevance. A review of the available data in PD provides the following evidence in support of this hypothesis: (i) an increase of iron in the brain, which in PD selectively involves neuromelanin in substantia nigra (SN) neurons; (ii) decreased availability of glutathione (GSH) and other antioxidant substances; (iii) increase of lipid peroxidation products and reactive oxygen (O2)species (ROS); and (iv) impaired mitochondrial electron transport mechanisms. Most of these changes appear to be closely related to interactions between iron and neuromelanin, which result in accumulation of iron and a continuous production of cytotoxic species leading to neuronal death. Some of these findings have been reproduced in animal models using 6-hydroxydopamine, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), iron loading and beta-carbolines, although none of them is an accurate model for PD in humans. Although it is not clear whether iron accumulation and oxidative stress are the initial events causing cell death or consequences of the disease process, therapeutic efforts aimed at preventing or at least delaying disease progression by reducing the overload of iron and generation of ROS may be beneficial in PD and related neurodegenerative disorders. Current pharmacotherapy of PD, in addition to symptomatic levodopa treatment, includes 'neuroprotective' strategies with dopamine agonists, monoamine oxidase-B inhibitors (MAO-B), glutamate antagonists, catechol O-methyltransferase inhibitors and other antioxidants or free radical scavengers. In the future, these agents could be used in combination with, or partly replaced by, iron chelators and lazaroids that prevent iron-induced generation of deleterious substances. Although experimental and preclinical data suggest the therapeutic potential of these drugs, their clinical applicability will be a major challenge for future research.
机译：虽然帕金森病（Pd）和相关神经退行性疾病的疾病仍然是未知的，但最近来自人和实验动物模型的证据表明，铁代谢的误解，铁诱导的氧化胁迫和自由基形成是主要的致病因子。这些因素触发了导致神经元死亡和随后的临床相关性的生化干扰的级联。对PD中的可用数据的审查提供了以下证据，以支持这一假设：（i）脑中的铁的增加，在Pd中选择性地涉及神经元蛋白在IndicaIa nigra（Sn）神经元中的核心; （ii）减少谷胱甘肽（GSH）和其他抗氧化物质的可用性; （iii）脂质过氧化产物的增加和反应性氧（O2）物种（ROS）; （IV）受损的线粒体电子传输机制。大多数这些变化似乎与铁和神经蛋白蛋白之间的相互作用密切相关，这导致铁的积累和连续生产导致神经元死亡的细胞毒性物种。使用6-羟基多胺，N-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP），铁荷载和β-粘土，虽然它们都是准确的人类PD模型。虽然尚不清楚铁积累和氧化应激是否是导致细胞死亡或疾病过程后果的初始事件，但旨在通过减少铁和生成RO的过载来预防或至少延迟疾病进展的治疗努力可能是有益的PD和相关神经变性障碍。目前PD的药物治疗除了症状左旋多巴治疗外，包括与多巴胺激动剂的“神经保护性”策略，单胺氧化酶-B抑制剂（MAO-B），谷氨酸拮抗剂，儿茶酚O-甲基转移酶抑制剂和其他抗氧化剂或自由基清除剂。将来，这些药剂可以与防止铁诱导的有害物质产生的铁螯合剂和褐发化剂组合使用或部分代替。虽然实验和临床前的数据表明这些药物的治疗潜力，但它们的临床适用性将是未来研究的主要挑战。

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