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\begin{document}

\title{Trilobatin attenuates cerebral ischemia/reperfusion-induced
blood-brain-barrier dysfunction by targeting MMP9: The legend of a food
additive}



\author[1]{Linying Feng}%
\author[1]{Yeli Li}%
\author[1]{Mu Lin }%
\author[1]{Dianyou Xie}%
\author[1]{Yunmei Luo}%
\author[2]{Zhi-Xu He}%
\author[2]{Qihai Gong}%
\author[1]{zhu yizhun}%
\author[2]{Jianmei Gao}%
\affil[1]{Macau University of Science and Technology}%
\affil[2]{Zunyi Medical University}%


\vspace{-1em}



  
  \date{May 13, 2024}


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\begin{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-\selectlanguage{greek}κ\selectlanguage{english}B), 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-\selectlanguage{greek}κ\selectlanguage{english}B axis.%
\end{abstract}%



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