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Trilobatin attenuates cerebral ischemia/reperfusion-induced blood-brain-barrier dysfunction by targeting MMP9: The legend of a food additive
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  • Linying Feng,
  • Yeli Li,
  • Mu Lin ,
  • Dianyou Xie,
  • Yunmei Luo,
  • Zhi-Xu He,
  • Qihai Gong,
  • zhu yizhun,
  • Jianmei Gao
Linying Feng
Macau University of Science and Technology
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Yeli Li
Macau University of Science and Technology
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Mu Lin
Macau University of Science and Technology
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Dianyou Xie
Macau University of Science and Technology
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Yunmei Luo
Macau University of Science and Technology
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Zhi-Xu He
Zunyi Medical University
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Qihai Gong
Zunyi Medical University
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zhu yizhun
Macau University of Science and Technology
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Jianmei Gao
Zunyi Medical University

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Abstract

Background and Purpose: Blood-brain barrier (BBB) breakdown is one of the most crucial pathological changes of cerebral ischemia-reperfusion (I/R) injury. Trilobatin (TLB), a naturally occurring food additive, exerts neuroprotective effect against cerebral I/R injury as demonstrated in our previous study. This study was designed to investigate the effect of TLB on disruption of BBB after cerebral I/R injury. Experimental Approach: Rats with focal cerebral ischemia caused by transient middle cerebral artery occlusion (MCAO) and brain microvascular endothelial cells along with human astrocytes to mimic blood brain barrier (BBB) injury caused by oxygen and glucose deprivation (OGD) followed by reoxygenation (OGD/R). Key results: The results showed that TLB effectively maintained the integrity of BBB and inhibited neuronal loss following cerebral I/R challenge. Furthermore, TLB dramatically increased tight junction proteins including ZO-1, occludin and claudin 5, as well as decreased the levels of apolipoprotein E (APOE) 4, cyclophilin A (CypA), and phosphorylated nuclear factor kappa B (NF-κB), thereby reduced proinflammatory cytokines. In addition, TLB also decreased Bax/Bcl-2 ratio and cleaved-caspase 3 level along with reduced the number of apoptotic neurons. Intriguingly, molecular docking and transcriptomics predicted MMP9 was a prominent gene evoked by TLB treatment. Furthermore, the protective effect of TLB on OGD/R-induced the loss of BBB integrity in human brain microvascular endothelial cell and astrocyte co-cultures in vitro was markedly reinforced by knockdown of MMP9. Conclusions and implications: Our findings reveal a novel property of TLB: saving BBB disruption following cerebral I/R via targeting MMP9 and inhibiting APOE4/CypA/NF-κB axis.
09 Feb 2023Submitted to British Journal of Pharmacology
15 Feb 2023Submission Checks Completed
15 Feb 2023Assigned to Editor
16 Feb 2023Review(s) Completed, Editorial Evaluation Pending
21 Feb 2023Reviewer(s) Assigned
27 Mar 2023Editorial Decision: Revise Minor
04 Jun 20231st Revision Received
24 Jun 2023Review(s) Completed, Editorial Evaluation Pending
24 Jun 2023Submission Checks Completed
24 Jun 2023Assigned to Editor
06 Jul 2023Reviewer(s) Assigned
13 Aug 2023Editorial Decision: Revise Minor
21 Aug 20232nd Revision Received
21 Aug 2023Submission Checks Completed
21 Aug 2023Assigned to Editor
21 Aug 2023Review(s) Completed, Editorial Evaluation Pending
05 Sep 2023Editorial Decision: Accept