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Trilobatin attenuates blood-brain barrier dysfunction induced by cerebral ischemia reperfusion by targeting MMP9: Involvement of APOE4/CypA/NF-κB signaling
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  • Linying Feng,
  • Yeli Li,
  • Mu Lin ,
  • Dianyou Xie,
  • Yunmei Luo,
  • Nana Chen,
  • Zhi-Xu He,
  • Qihai Gong,
  • zhu yizhun,
  • Jianmei Gao
Linying Feng
Macau University of Science and Technology

Corresponding Author:[email protected]

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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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Nana Chen
Zunyi Medical University
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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.