Daidzein Augments Cholesterol Homeostasis via ApoE to Promote Functional Recovery in Chronic Stroke
Daidzein Augments Cholesterol Homeostasis via ApoE to Promote Functional Recovery in Chronic Stroke
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DOI：
10.1523/jneurosci.2890-15.2015
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发表时间：
2015-11-11
影响因子：
5.3
通讯作者：
Cho, Sunghee
中科院分区：
文献类型：
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作者：
Kim, Eunhee;Woo, Moon-Sook;Cho, Sunghee
中风是世界上导致生理残疾的主要原因，但目前还没有可用的药物可以在中风后早期递送以促进恢复。大豆黄酮，一种大豆黄酮，是一种临床批准的药物，在体外具有神经保护作用，它促进视神经挤压动物模型中轴突的生长。目前的研究探讨了大豆黄酮对中风恢复的临床相关小鼠模型的神经保护和功能恢复的功效。鉴于胆固醇是损伤诱导的突触重塑中必不可少的脂质底物这一事实，我们发现大豆黄酮在体外增强了胆固醇稳态遗传程序，包括Lxr和下游转运蛋白、Apoe、Abca 1和Abcg 1基因。大豆黄酮还提高了中风后脑中的胆固醇稳态基因，其中Apoe是表达最高的转运蛋白，但不影响梗死体积或半球肿胀。尽管缺乏神经保护，大豆黄酮改善运动/步态功能在慢性中风和突触素表达升高。然而，大豆苷元增强的功能益处和突触素表达在ApoE基因敲除小鼠中被消除，这表明大豆苷元诱导的ApoE上调在促进中风恢复中的重要性。大豆苷元诱导的功能性益处与神经保护的缺乏之间的分离进一步表明，与急性病理学相比，恢复过程中存在非重叠机制。由于其在人类中已知的安全性，旨在增加ApoE的大豆黄酮的早期和长期使用可能作为一种新的，可翻译的策略，以促进中风患者的功能恢复，而没有不良的急性影响。
Stroke is the world's leading cause of physiological disability, but there are currently no available agents that can be delivered early after stroke to enhance recovery. Daidzein, a soy isoflavone, is a clinically approved agent that has a neuroprotective effect in vitro, and it promotes axon growth in an animal model of optic nerve crush. The current study investigates the efficacy of daidzein on neuroprotection and functional recovery in a clinically relevant mouse model of stroke recovery. In light of the fact that cholesterols are essential lipid substrates in injury-induced synaptic remodeling, we found that daidzein enhanced the cholesterol homeostasis genetic program, including Lxr and downstream transporters, Apoe, Abca1, and Abcg1 genes in vitro. Daidzein also elevated the cholesterol homeostasis genes in the poststroke brain with Apoe, the highest expressing transporter, but did not affect infarct volume or hemispheric swelling. Despite the absence of neuroprotection, daidzein improved motor/gait function in chronic stroke and elevated synaptophysin expression. However, the daidzein-enhanced functional benefits and synaptophysin expression were abolished in Apoe-knock-out mice, suggesting the importance of daidzein-induced ApoE upregulation in fostering stroke recovery. Dissociation between daidzein-induced functional benefits and the absence of neuroprotection further suggest the presence of nonoverlapping mechanisms underlying recovery processes versus acute pathology. With its known safety in humans, early and chronic use of daidzein aimed at augmenting ApoE may serve as a novel, translatable strategy to promote functional recovery in stroke patients without adverse acute effect.