Edaravone alleviates Alzheimer's disease-type pathologies and cognitive deficits
Edaravone alleviates Alzheimer's disease-type pathologies and cognitive deficits
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DOI：
10.1073/pnas.1422998112
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发表时间：
2015-04-21
影响因子：
11.1
通讯作者：
Wang, Yan-Jiang
中科院分区：
文献类型：
--
作者：
Jiao, Shu-Sheng;Yao, Xiu-Qing;Wang, Yan-Jiang
阿尔茨海默病（AD）是影响老年人的最具破坏性的疾病之一。淀粉样蛋白- β (A β)的积累和氧化应激等下游病理事件在AD的发病机制中起关键作用。当前临床试验失败的教训表明，针对阿尔茨海默病发病机制的多个关键途径是阻止疾病进展所必需的。在这里，我们展示了依达拉奉，一种用于急性缺血性中风的自由基清除剂，在体外具有抑制a β聚集和减弱a β诱导氧化的有效能力。在A β沉积发生之前或之后通过腹腔注射给药，依达拉单可显著减少A β沉积，减轻氧化应激，减轻下游病理包括Tau过度磷酸化、胶质活化、神经炎症、神经元丧失、突触功能障碍，并挽救APPswe/PS1小鼠的行为缺陷。口服依达拉奉还能改善ad样病理和小鼠的记忆缺陷。这些发现表明，依达拉奉通过靶向疾病发病机制的多个关键途径，有望成为阿尔茨海默病的治疗药物。
Alzheimer's disease (AD) is one of most devastating diseases affecting elderly people. Amyloid-beta (A beta) accumulation and the downstream pathological events such as oxidative stress play critical roles in pathogenesis of AD. Lessons from failures of current clinical trials suggest that targeting multiple key pathways of the AD pathogenesis is necessary to halt the disease progression. Here we show that Edaravone, a free radical scavenger that is marketed for acute ischemic stroke, has a potent capacity of inhibiting A beta aggregation and attenuating A beta-induced oxidation in vitro. When given before or after the onset of A beta deposition via i.p. injection, Edaravone substantially reduces A beta deposition, alleviates oxidative stress, attenuates the downstream pathologies including Tau hyperphosphorylation, glial activation, neuroinflammation, neuronal loss, synaptic dysfunction, and rescues the behavioral deficits of APPswe/PS1 mice. Oral administration of Edaravone also ameliorates the AD-like pathologies and memory deficits of the mice. These findings suggest that Edaravone holds a promise as a therapeutic agent for AD by targeting multiple key pathways of the disease pathogenesis.