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Article: Levofloxacin alleviates blood-brain barrier disruption following cerebral ischemia and reperfusion via directly inhibiting A-FABP.

TitleLevofloxacin alleviates blood-brain barrier disruption following cerebral ischemia and reperfusion via directly inhibiting A-FABP.
Authors
KeywordsA-FABP
Blood-brain barrier
Ischemic stroke
Neuroinflammation
Reperfusion injury
Issue Date15-Jan-2024
PublisherElsevier
Citation
European Journal of Pharmacology, 2024, v. 963 How to Cite?
AbstractReperfusion therapy is currently the most effective treatment for acute ischemic stroke, but often results in secondary brain injury. Adipocyte fatty acid-binding protein (A-FABP, FABP4, or aP2) was shown to critically mediate cerebral ischemia/reperfusion (I/R) injury by exacerbating blood-brain barrier (BBB) disruption. However, no A-FABP inhibitors have been approved for clinical use due to safety issues. Here, we identified the therapeutic effect of levofloxacin, a widely used antibiotic displaying A-FABP inhibitory activity in vitro, on cerebral I/R injury and determined its target specificity and action mechanism in vivo. Using molecular docking and site-directed mutagenesis, we showed that levofloxacin inhibited A-FABP activity through interacting with the amino acid residue Asp76, Gln95, Arg126 of A-FABP. Accordingly, levofloxacin significantly inhibited A-FABP-induced JNK phosphorylation and expressions of proinflammatory factors and matrix metalloproteinase 9 (MMP-9) in mouse primary macrophages. In wild-type mice with transient middle cerebral artery occlusion, levofloxacin substantially mitigated BBB disruption and neuroinflammation, leading to reduced cerebral infarction, alleviated neurological outcomes, and improved survival. Mechanistically, levofloxacin decreased MMP-9 expression and activity, and thus reduced degradation of extracellular matrix and endothelial tight junction proteins. Importantly, the BBB- and neuro-protective effects of levofloxacin were abolished in A-FABP or MMP-9 knockout mice, suggesting that the therapeutic effects of levofloxacin highly depended on specific targeting of the A-FABP-MMP-9 axis. Overall, our study demonstrates that levofloxacin alleviates A-FABP-induced BBB disruption and neural tissue injury following cerebral I/R, and unveils its therapeutic potential for the treatment of ischemic stroke.
Persistent Identifierhttp://hdl.handle.net/10722/339856
ISSN
2023 Impact Factor: 4.2
2023 SCImago Journal Rankings: 1.055
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorYang, S-
dc.contributor.authorXu, D-
dc.contributor.authorZhang, D-
dc.contributor.authorHuang, X-
dc.contributor.authorLi, S-
dc.contributor.authorWang, Y-
dc.contributor.authorLu, J-
dc.contributor.authorWang, D-
dc.contributor.authorGuo, ZN-
dc.contributor.authorYang, Y-
dc.contributor.authorYe, D-
dc.contributor.authorWang, Y-
dc.contributor.authorXu, A-
dc.contributor.authorHoo, RLC-
dc.contributor.authorChang, J-
dc.date.accessioned2024-03-11T10:39:48Z-
dc.date.available2024-03-11T10:39:48Z-
dc.date.issued2024-01-15-
dc.identifier.citationEuropean Journal of Pharmacology, 2024, v. 963-
dc.identifier.issn0014-2999-
dc.identifier.urihttp://hdl.handle.net/10722/339856-
dc.description.abstractReperfusion therapy is currently the most effective treatment for acute ischemic stroke, but often results in secondary brain injury. Adipocyte fatty acid-binding protein (A-FABP, FABP4, or aP2) was shown to critically mediate cerebral ischemia/reperfusion (I/R) injury by exacerbating blood-brain barrier (BBB) disruption. However, no A-FABP inhibitors have been approved for clinical use due to safety issues. Here, we identified the therapeutic effect of levofloxacin, a widely used antibiotic displaying A-FABP inhibitory activity in vitro, on cerebral I/R injury and determined its target specificity and action mechanism in vivo. Using molecular docking and site-directed mutagenesis, we showed that levofloxacin inhibited A-FABP activity through interacting with the amino acid residue Asp76, Gln95, Arg126 of A-FABP. Accordingly, levofloxacin significantly inhibited A-FABP-induced JNK phosphorylation and expressions of proinflammatory factors and matrix metalloproteinase 9 (MMP-9) in mouse primary macrophages. In wild-type mice with transient middle cerebral artery occlusion, levofloxacin substantially mitigated BBB disruption and neuroinflammation, leading to reduced cerebral infarction, alleviated neurological outcomes, and improved survival. Mechanistically, levofloxacin decreased MMP-9 expression and activity, and thus reduced degradation of extracellular matrix and endothelial tight junction proteins. Importantly, the BBB- and neuro-protective effects of levofloxacin were abolished in A-FABP or MMP-9 knockout mice, suggesting that the therapeutic effects of levofloxacin highly depended on specific targeting of the A-FABP-MMP-9 axis. Overall, our study demonstrates that levofloxacin alleviates A-FABP-induced BBB disruption and neural tissue injury following cerebral I/R, and unveils its therapeutic potential for the treatment of ischemic stroke.-
dc.languageeng-
dc.publisherElsevier-
dc.relation.ispartofEuropean Journal of Pharmacology-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectA-FABP-
dc.subjectBlood-brain barrier-
dc.subjectIschemic stroke-
dc.subjectNeuroinflammation-
dc.subjectReperfusion injury-
dc.titleLevofloxacin alleviates blood-brain barrier disruption following cerebral ischemia and reperfusion via directly inhibiting A-FABP.-
dc.typeArticle-
dc.identifier.doi10.1016/j.ejphar.2023.176275-
dc.identifier.pmid38113968-
dc.identifier.scopuseid_2-s2.0-85180574005-
dc.identifier.volume963-
dc.identifier.eissn1879-0712-
dc.identifier.isiWOS:001144068900001-
dc.identifier.issnl0014-2999-

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