European journal of pharmacology · 2025
Rosmarinic acid attenuates blood-brain barrier dysfunction to improve cerebral ischemia/reperfusion injury in mice.
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Guo Chao, Li Jianbo, Liao Yucheng, Yin Ying, Ma Zhongying, Liang Shan, Quan Wei, Wang Jingwen
Аннотация
BACKGROUND: Cerebral ischemia/reperfusion (CI/R) has detrimental effects in cases of ischemic stroke. This notably triggers the blood-brain-barrier (BBB) to break. Known for its ability to provide neuroprotective benefits, rosmarinic acid (RosA) is a phenolic acid compound in the Lamiaceae family of plants. However, the relevance between the neuroprotective effect of RosA on CI/R and its direct protective effect on the BBB remains unclear. This study aimed to investigate how RosA regulates BBB integrity after CI/R injury and explore its underlying pharmacological mechanism in mice.
METHODS: The mouse model of middle cerebral artery occlusion (MCAO) was established by subjecting the animals to 1 h of ischemia followed by a 24-h reperfusion period. Neurological scoring, infarct size, BBB permeability, histological examination, and biochemical parameters were subsequently assessed.
RESULTS: Our study showed that RosA improved neurofunction and reduced infarct size by protecting BBB permeability, alleviating CI/R-induced neuronal loss and apoptosis. Molecular docking, molecular dynamics (MD) simulationand surface plasmon resonance (SPR) suggested that RosA may directly bind to matrix metalloproteinase-9 (MMP-9) and matrix metalloproteinase-2 (MMP-2). Furthermore, RosA significantly enhanced tight junction proteins, including zonula occludens-1 (ZO-1), occludin and claudin 5, while simultaneously decreasing the levels of MMP-9 and MMP-2 mRNA and proteins.
CONCLUSION: Our findings reveal that RosA significantly mitigates CI/R-induced BBB disruption in middle cerebral artery occlusion (MCAO) mice by enhancing tight junction protein expression and down-regulating MMP-9 and MMP-2 levels.
METHODS: The mouse model of middle cerebral artery occlusion (MCAO) was established by subjecting the animals to 1 h of ischemia followed by a 24-h reperfusion period. Neurological scoring, infarct size, BBB permeability, histological examination, and biochemical parameters were subsequently assessed.
RESULTS: Our study showed that RosA improved neurofunction and reduced infarct size by protecting BBB permeability, alleviating CI/R-induced neuronal loss and apoptosis. Molecular docking, molecular dynamics (MD) simulationand surface plasmon resonance (SPR) suggested that RosA may directly bind to matrix metalloproteinase-9 (MMP-9) and matrix metalloproteinase-2 (MMP-2). Furthermore, RosA significantly enhanced tight junction proteins, including zonula occludens-1 (ZO-1), occludin and claudin 5, while simultaneously decreasing the levels of MMP-9 and MMP-2 mRNA and proteins.
CONCLUSION: Our findings reveal that RosA significantly mitigates CI/R-induced BBB disruption in middle cerebral artery occlusion (MCAO) mice by enhancing tight junction protein expression and down-regulating MMP-9 and MMP-2 levels.