5-lipoxygenase pathway and its downstream cysteinyl leukotrienes as potential therapeutic targets for Alzheimer's disease
5-lipoxygenase pathway and its downstream cysteinyl leukotrienes as potential therapeutic targets for Alzheimer's disease
复制标题
5-脂氧合酶途径及其下游半胱氨酰白三烯作为阿尔茨海默病的潜在治疗靶点
DOI：
10.1016/j.bbi.2020.03.022
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发表时间：
2020-08-01
影响因子：
15.1
通讯作者：
Tang, Susu
中科院分区：
文献类型：
--
作者：
Chen, Fang;Ghosh, Arijit;Tang, Susu
5-脂氧合酶（ALOX 5）是一种参与花生四烯酸（AA）代谢的酶，花生四烯酸代谢是一种代谢途径，其中半胱氨酰白三烯（CysLT）是所得代谢物。AL 0X 5和CysLT两者在许多炎性疾病中具有临床意义，例如在哮喘和过敏性鼻炎中，并且拮抗这些分子的作用的药物长期以来已成功地用于对抗这些疾病。有趣的是，“神经炎症”研究的最新进展导致发现了几种调节许多大脑病理的新炎症通路，包括ALOX 5通路。通过药理学和遗传学研究，已经显示ALOX 5和CysLTs受体都参与阿尔茨海默病（AD）和其他神经退行性/神经系统疾病（例如帕金森病、多发性硬化和癫痫）的发病机制。在AD的转基因和散发性模型中，已经表明AL 0X 5/CysLT的水平升高，并且这些分子的遗传/药理学干预可以减轻AD相关的行为和病理状况。在AD脑样品中也发现了这些分子的临床相关性。在这篇综述中，我们的目的是总结ALOX 5/CysLTs在AD病理生理学中的作用，从细胞和分子方面的重要发现，并讨论其阻断剂作为可能的治疗选择，以遏制AD相关的条件的潜力。
5-lipoxygenase (ALOX5) is an enzyme involved in arachidonic acid (AA) metabolism, a metabolic pathway in which cysteinyl leukotrienes (CysLTs) are the resultant metabolites. Both ALOX5 and CysLTs are clinically significant in a number of inflammatory diseases, such as in asthma and allergic rhinitis, and drugs antagonizing the effect of these molecules have long been successfully used to counter these diseases. Interestingly, recent advances in 'neuroinflammation' research has led to the discovery of several novel inflammatory pathways regulating many cerebral pathologies, including the ALOX5 pathway. By means of pharmacological and genetic studies, both ALOX5 and CysLTs receptors have been shown to be involved in the pathogenesis of Alzheimer's disease (AD) and other neurodegenerative/neurological diseases, such as in Parkinson's disease, multiple sclerosis, and epilepsy. In both transgenic and sporadic models of AD, it has been shown that the levels of ALOX5/CysLTs are elevated, and that genetic/pharmacological interventions of these molecules can alleviate AD-related behavioral and pathological conditions. Clinical relevance of these molecules has also been found in AD brain samples. In this review, we aim to summarize such important findings on the role of ALOX5/CysLTs in AD pathophysiology, from both the cellular and the molecular aspects, and also discuss the potential of their blockers as possible therapeutic choices to curb AD-related conditions.