Kim Eunhee, Woo Moon-Sook, Qin Luye, Ma Thong, Beltran Cesar D, Bao Yi, Bailey Jason A, Corbett Dale, Ratan Rajiv R, Lahiri Debomoy K, Cho Sunghee
Burke-Cornell Medical Research Institute, White Plains, New York 10605, Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, New York 10021.
Burke-Cornell Medical Research Institute, White Plains, New York 10605.
J Neurosci. 2015 Nov 11;35(45):15113-26. doi: 10.1523/JNEUROSCI.2890-15.2015.
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.
There have been recurring translational failures in treatment strategies for stroke. One underlying issue is the disparity in outcome analysis between animal and clinical studies. The former mainly depends on acute infarct size, whereas long-term functional recovery is an important outcome in patients. In an attempt to identify agents that promote functional recovery, we discovered that an FDA-approved soy isoflavone, daidzein, improved stroke-induced behavioral deficits via enhancing cholesterol homeostasis in chronic stroke, and this occurs without causing adverse effects in the acute phase. With its known safety in humans, the study suggests that the early and chronic use of daidzein serves as a potential strategy to promote functional recovery in stroke patients.
中风是全球生理残疾的主要原因，但目前尚无能够在中风后早期给药以促进恢复的药物。大豆异黄酮黄豆苷元是一种临床批准的药物，在体外具有神经保护作用，并且在视神经挤压动物模型中能促进轴突生长。本研究调查了黄豆苷元在具有临床相关性的中风恢复小鼠模型中对神经保护和功能恢复的疗效。鉴于胆固醇是损伤诱导的突触重塑中必需的脂质底物，我们发现黄豆苷元在体外增强了胆固醇稳态遗传程序，包括肝X受体（Lxr）及其下游转运蛋白、载脂蛋白E（Apoe）、三磷酸腺苷结合盒转运蛋白A1（Abca1）和三磷酸腺苷结合盒转运蛋白G1（Abcg1）基因。黄豆苷元还提高了中风后大脑中胆固醇稳态基因的表达，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。尽管没有神经保护作用，但黄豆苷元改善了慢性中风小鼠的运动/步态功能，并提高了突触素的表达。然而，在载脂蛋白E基因敲除小鼠中，黄豆苷元增强的功能益处和突触素表达被消除，这表明黄豆苷元诱导的载脂蛋白E上调在促进中风恢复中具有重要作用。黄豆苷元诱导的功能益处与缺乏神经保护作用之间的分离进一步表明，恢复过程与急性病理过程背后存在不重叠的机制。鉴于其在人类中的已知安全性，早期和长期使用黄豆苷元以增加载脂蛋白E水平，可能成为一种新颖的、可转化的策略，以促进中风患者的功能恢复且无不良急性效应。
中风治疗策略中反复出现转化失败的情况。一个潜在问题是动物研究和临床研究在结果分析上存在差异。前者主要依赖急性梗死大小，而长期功能恢复是患者的重要结局。为了确定促进功能恢复的药物，我们发现一种经美国食品药品监督管理局（FDA）批准的大豆异黄酮黄豆苷元，通过增强慢性中风中的胆固醇稳态改善了中风引起的行为缺陷，并且在急性期不会产生不良影响。鉴于其在人类中的已知安全性，该研究表明早期和长期使用黄豆苷元是促进中风患者功能恢复的潜在策略。
