title: Daidzein Augments Cholesterol Homeostasis via ApoE to Promote Functional Recovery in Chronic Stroke.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.
authors.forename: Eunhee
authors.initials: E
authors.lastname: Kim
authors.affiliation: Burke-Cornell Medical Research Institute, White Plains, New York 10605.
authors.forename: Moon-Sook
authors.initials: MS
authors.lastname: Woo
authors.affiliation: Burke-Cornell Medical Research Institute, White Plains, New York 10605.
authors.forename: Luye
authors.initials: L
authors.lastname: Qin
authors.affiliation: Burke-Cornell Medical Research Institute, White Plains, New York 10605.
authors.forename: Thong
authors.initials: T
authors.lastname: Ma
authors.affiliation: Burke-Cornell Medical Research Institute, White Plains, New York 10605.
authors.forename: Cesar D
authors.initials: CD
authors.lastname: Beltran
authors.affiliation: Burke-Cornell Medical Research Institute, White Plains, New York 10605.
authors.forename: Yi
authors.initials: Y
authors.lastname: Bao
authors.affiliation: Institute of Psychiatric Research, Department of Psychiatry, Neuroscience Research Center, Indiana University School of Medicine, Indianapolis, Indiana 46202, and.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Bailey
authors.affiliation: Heart and Stroke Foundation Canadian Partnership for Stroke Recovery, University of Ottawa and University of Toronto, Ottawa, Ontario K1G 5Z3, Canada.
authors.forename: Dale
authors.identifier: http://orcid.org/0000-0003-0217-4576
authors.initials: D
authors.lastname: Corbett
authors.affiliation: 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.
authors.forename: Rajiv R
authors.identifier: http://orcid.org/0000-0002-9081-2701
authors.initials: RR
authors.lastname: Ratan
authors.affiliation: Institute of Psychiatric Research, Department of Psychiatry, Neuroscience Research Center, Indiana University School of Medicine, Indianapolis, Indiana 46202, and.
authors.forename: Debomoy K
authors.initials: DK
authors.lastname: Lahiri
authors.affiliation: 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, suc2002@med.cornell.edu.
authors.forename: Sunghee
authors.initials: S
authors.lastname: Cho
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000502:physiology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002784:Cholesterol / Q000502:physiology*; D002908:Chronic Disease; D006131:Growth Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006706:Homeostasis / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007529:Isoflavones / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020127:Recovery of Function / Q000187:drug effects* / Q000502:physiology; D020521:Stroke / Q000188:drug therapy* / Q000503:physiopathology
chemical_list: D001057:Apolipoproteins E; D006131:Growth Inhibitors; D007529:Isoflavones; C004742:daidzein; D002784:Cholesterol
keywords: ApoE; cholesterol transporter; daidzein; motor/gait function; stroke recovery