DL-3n-Butylphthalide Improves Blood–Brain Barrier Integrity in Rat After Middle Cerebral Artery Occlusion
Open Access
- 12 January 2021
- journal article
- research article
- Published by Frontiers Media SA in Frontiers in Cellular Neuroscience
Abstract
Objective: DL-3n-butylphthalide (NBP) has beneficial effects in different stages of ischemic stroke. Our previous studies have demonstrated that NBP promoted angiogenesis in the perifocal region of the ischemic brain. However, the molecular mechanism of NBP for blood–brain barrier protection in acute ischemic stroke was unclear. Here, we explored the neuroprotective effects of NBP on blood–brain barrier integrity in the acute phase of ischemic stroke in a rat model. Methods: Adult male Sprague–Dawley rats (n = 82) underwent 2 h of transient middle cerebral artery occlusion and received 90 mg/kg of NBP for 3 days. Brain edema, infarct volume, surface blood flow, and neurological severity score were evaluated. Blood–brain barrier integrity was evaluated by Evans blue leakage and changes in tight junction proteins. We further examined AQP4 and eNOS expression, MMP-9 enzyme activity, and possible signaling pathways for the role of NBP after ischemic stroke. Results: NBP treatment significantly increased eNOS expression and surface blood flow in the brain, reduced brain edema and infarct volume, and improved neurological severity score compared to the control group (p < 0.05). Furthermore, NBP attenuated Evans blue and IgG leakage and increased tight junction protein expression compared to the control after 1 and 3 days of ischemic stroke (p < 0.05). Finally, NBP decreased AQP4 expression, MMP-9 enzyme activity, and increased MAPK expression during acute ischemic stroke. Conclusion: NBP protected blood–brain barrier integrity and attenuated brain injury in the acute phase of ischemic stroke by decreasing AQP4 expression and MMP-9 enzyme activity. The MAPK signaling pathway may be associated in this process.Funding Information
- National Key Research and Development Program of China (2016YFC1300600)
- National Natural Science Foundation of China (81870921, 81771244, 81771251, 81771281, 81801170, 81974179)
- K. C. Wong Education Foundation (GYY)
- Shanghai Municipal Education Commission (2019-01-07-00-02-E00064)
This publication has 50 references indexed in Scilit:
- Surgery-Related Thrombosis Critically Affects the Brain Infarct Volume in Mice Following Transient Middle Cerebral Artery OcclusionPLOS ONE, 2013
- Matrix Metalloproteinases and Blood-Brain Barrier Disruption in Acute Ischemic StrokeFrontiers in Neurology, 2013
- Hydrogen sulfide and nitric oxide are mutually dependent in the regulation of angiogenesis and endothelium-dependent vasorelaxationProceedings of the National Academy of Sciences of the United States of America, 2012
- Blood–Brain Barrier Breakdown in Acute and Chronic Cerebrovascular DiseaseStroke, 2011
- Design, synthesis and evaluation of nitric oxide releasing derivatives of 3-n-butylphthalide as antiplatelet and antithrombotic agentsOrganic & Biomolecular Chemistry, 2011
- dl-3-n-Butylphthalide prevents neuronal cell death after focal cerebral ischemia in mice via the JNK pathwayBrain Research, 2010
- Random process estimator for laser speckle imaging of cerebral blood flowOptics Express, 2009
- 实体瘤细胞中低氧诱导因子-1蛋白的活性调控Chinese Science Bulletin (Chinese Version), 2009
- MMP-9–Positive Neutrophil Infiltration Is Associated to Blood–Brain Barrier Breakdown and Basal Lamina Type IV Collagen Degradation During Hemorrhagic Transformation After Human Ischemic StrokeStroke, 2008
- The Role of Aquaporin-4 Polymorphisms in the Development of Brain Edema After Middle Cerebral Artery OcclusionStroke, 2008