Dl-3-n-butylphthalide protects the blood brain barrier of cerebral infarction by activating the Nrf-2/HO-1 signaling pathway in mice

Y.-J. Zhao, Y. Nai, Q.-S. Ma, D.-J. Song, Y.-B. Ma, L.-H. Zhang, L.-X. Mi

Department of Neurology, Yantai Yuhuangding Hospital, Shandong, China. aiqiangel@yeah.ne

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• Pharmacology

OBJECTIVE: The aim of this study was to explore whether Dl-3-n-butylphthalide (DBT) could protect blood-brain barrier (BBB) of mice with experimental cerebral infarction and the relevant mechanism.

MATERIALS AND METHODS: Adult male CD-1 mice were selected as the study objects. The permanent middle cerebral artery occlusion (MCAO) model was prepared by Longa’s modified suture-occluded method. The mice were randomly divided into 3 groups: the sham operation group (Sham group), the cerebral infarction model group (CI group) and the DBT (120 mg/kg) intervention group (DBT group). Neurologic function deficits were evaluated by Longa’s modified scoring method after 24 h of permanent MCAO. The wet and dry weight method was used for measuring water content in brain tissues. 2% 2,3,5-triphenyltetrazolium chloride (TTC) staining method was applied to determine the volume of cerebral infarction. Changes in the protein and messenger ribonucleic acid (mRNA) expression levels of matrix metallopeptidase 9 (MMP-9), claudin-5, vascular endothelial growth factor (VEGF), glial fibrillary acidic protein (GFAP), NF-E2 related factor 2 (Nrf-2) and heme oxygenase 1 (HO-1) in ischemic brain tissues were detected using immunohistochemistry, Western blotting and quantitative Reverse Transcription-Polymerase Chain Reaction (qRT-PCR). Ultrastructure changes in BBBs were observed under an electron microscope.

RESULTS: DBT improved the neurologic function deficits of mice and reduced the infarction volume of mice with cerebral infarction. DBT alleviated edema and decreased the permeability of BBBs of mice with cerebral infarction. DBT down-regulated the expression of MMP-9 and up-regulated the expression of claudin-5 in brain tissues of mice with cerebral infarction. DBT increased the expressions of VEGF and GFAP. DBT improved the ultrastructure in capillary endothelial cells of BBBs and increased the expressions of Nrf-2 and HO-1.

CONCLUSIONS: DBT may protect BBB by activating the Nrf-2/HO-1 signaling pathway, thus achieving its protective effect on the brain.

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