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J Cereb Blood Flow Metab. 2019 Feb;39(2):352-366. doi: 10.1177/0271678X18764083. Epub 2018 Mar 13.

Protective effects of sulforaphane in experimental vascular cognitive impairment: Contribution of the Nrf2 pathway.

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1 Department of Neurology, School of Medicine, Pittsburgh Institute of Brain Disorders and Recovery, University of Pittsburgh, Pittsburgh, PA, USA.
2 Key Laboratory of Cerebral Microcirculation, Taishan Medical University, Tai'an, Shandong, China.
3 State Key Laboratory of Medical Neurobiology and Institute of Brain Science, Fudan University, Shanghai, China.

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The major pathophysiological process of vascular cognitive impairment (VCI) is chronic cerebral ischemia, which causes disintegration of the blood-brain barrier (BBB), neuronal death, and white matter injury. This study aims to test whether sulforaphane (Sfn), a natural activator of nuclear factor erythroid 2-related factor 2 (Nrf2), reduces the chronic ischemic injury and cognitive dysfunction after VCI. Experimental VCI was induced in rats by permanent occlusion of both common carotid arteries for six weeks. This procedure caused notable neuronal death in the cortex and hippocampal CA1, myelin loss in the corpus callosum and hippocampal fimbria, accumulation of myelin debris in the corpus callosum, and remarkable cognitive impairment. Sfn treatment alleviated these ischemic injuries and the cognitive dysfunction. Sfn-mediated neuroprotection was associated with enhanced activation of Nrf2 and upregulation of heme oxygenase 1. Sfn also reduced neuronal and endothelial death and maintained the integrity of BBB after oxygen-glucose deprivation in vitro in an Nrf2 dependent manner. Furthermore, Nrf2 knockdown in endothelial cells decreased claudin-5 protein expression with downregulated claudin-5 promoter activity, suggesting that claudin-5 might be a target gene of Nrf2. Our results demonstrate that Sfn provides robust neuroprotection against chronic brain ischemic injury and may be a promising agent for VCI treatment.


Dementia; hypoperfusion; ischemic tolerance; neurovascular unit; tight junction


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