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Daidzein Augments Cholesterol Homeostasis via ApoE to Promote Functional Recovery in Chronic Stroke.

TitleDaidzein Augments Cholesterol Homeostasis via ApoE to Promote Functional Recovery in Chronic Stroke.
Publication TypeJournal Article
Year of Publication2015
AuthorsKim E, Woo M-S, Qin L, Ma T, Beltran CD, Bao Y, Bailey JA, Corbett D, Ratan RR, Lahiri DK, Cho S
JournalJ Neurosci
Volume35
Issue45
Pagination15113-26
Date Published2015 Nov 11
ISSN1529-2401
KeywordsAnimals, Apolipoproteins E, Cell Line, Tumor, Cells, Cultured, Cholesterol, Chronic Disease, Growth Inhibitors, Homeostasis, Humans, Isoflavones, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Recovery of Function, Stroke
Abstract

UNLABELLED: 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.

SIGNIFICANCE STATEMENT: 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.

DOI10.1523/JNEUROSCI.2890-15.2015
Alternate JournalJ. Neurosci.
PubMed ID26558782
PubMed Central IDPMC4642242
Grant ListAG18379 / AG / NIA NIH HHS / United States
R01 AG018884 / AG / NIA NIH HHS / United States
R01 HL082511 / HL / NHLBI NIH HHS / United States
HL82511-04S1 / HL / NHLBI NIH HHS / United States
NS077897 / NS / NINDS NIH HHS / United States
R01 NS077897 / NS / NINDS NIH HHS / United States
R01 NS095359 / NS / NINDS NIH HHS / United States
R01 AG051086 / AG / NIA NIH HHS / United States
HL82511 / HL / NHLBI NIH HHS / United States
AG18884 / AG / NIA NIH HHS / United States
R01 AG018379 / AG / NIA NIH HHS / United States