Inhibition of fatty acid synthesis aggravates brain injury, reduces blood-brain barrier integrity and impairs neurological recovery in a murine stroke model

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dc.authorid0000-0002-6242-3709
dc.authorid0000-0001-6494-8923
dc.contributor.authorJanssen, Lisa
dc.contributor.authorAi, Xiaoyu
dc.contributor.authorZheng, Xuan
dc.contributor.authorWei, Wei
dc.contributor.authorÇağlayan, Ahmet Burak
dc.contributor.authorKılıç, Ertuğrul
dc.contributor.authorWang, Ya-chao
dc.contributor.authorHermann, Dirk M.
dc.contributor.authorVenkataramani, Vivek
dc.contributor.authorBaehr, Mathias
dc.contributor.authorDoeppner, Thorsten R.
dc.date.accessioned2021-09-16T08:34:50Z
dc.date.available2021-09-16T08:34:50Z
dc.date.issued2021
dc.departmentİstanbul Medipol Üniversitesi, Rektörlük, Rejeneratif ve Restoratif Tıp Araştırmaları Merkezi (REMER)
dc.description.abstractInhibition of fatty acid synthesis (FAS) stimulates tumor cell death and reduces angiogenesis. When SH-SY5Y cells or primary neurons are exposed to hypoxia only, inhibition of FAS yields significantly enhanced cell injury. The pathophysiology of stroke, however, is not only restricted to hypoxia but also includes reoxygenation injury. Hence, an oxygen-glucose-deprivation (OGD) model with subsequent reoxygenation in both SH-SY5Y cells and primary neurons as well as a murine stroke model were used herein in order to study the role of FAS inhibition and its underlying mechanisms. SH-SY5Y cells and cortical neurons exposed to 10 h of OGD and 24 h of reoxygenation displayed prominent cell death when treated with the Acetyl-CoA carboxylase inhibitor TOFA or the fatty acid synthase inhibitor cerulenin. Such FAS inhibition reduced the reduction potential of these cells, as indicated by increased NADH(2)(+)/NAD(+) ratios under both in vitro and in vivo stroke conditions. As observed in the OGD model, FAS inhibition also resulted in increased cell death in the stroke model. Stroke mice treated with cerulenin did not only display increased brain injury but also showed reduced neurological recovery during the observation period of 4 weeks. Interestingly, cerulenin treatment enhanced endothelial cell leakage, reduced transcellular electrical resistance (TER) of the endothelium and contributed to poststroke blood-brain barrier (BBB) breakdown. The latter was a consequence of the activated NF-kappa B pathway, stimulating MMP-9 and ABCB1 transporter activity on the luminal side of the endothelium. In conclusion, FAS inhibition aggravated poststroke brain injury as consequence of BBB breakdown and NF-kappa B-dependent inflammation.
dc.identifier.citationJanssen, L., Ai, X., Zheng, X., Wei, W., Çağlayan, A. B., Kılıç, E. ... Doeppner, T. R. (2021). Inhibition of fatty acid synthesis aggravates brain injury, reduces blood-brain barrier integrity and impairs neurological recovery in a murine stroke model. Frontiers in Cellular Neuroscience, 15. https://dx.doi.org/10.3389/fncel.2021.733973
dc.identifier.doi10.3389/fncel.2021.733973
dc.identifier.issn1662-5102
dc.identifier.scopusqualityQ1
dc.identifier.urihttps://dx.doi.org/10.3389/fncel.2021.733973
dc.identifier.urihttps://hdl.handle.net/20.500.12511/8191
dc.identifier.volume15
dc.identifier.wosqualityQ1
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.language.isoen
dc.publisherFrontiers Media SA
dc.relation.ispartofFrontiers in Cellular Neuroscienceen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsAttribution 4.0 International*
dc.rightsinfo:eu-repo/semantics/openAccess
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/*
dc.subjectBlood-Brain Barrier
dc.subjectCerebral Ischemia
dc.subjectFatty Acid Synthesis
dc.subjectHypoxia
dc.subjectNeuroprotection
dc.subjectReduction Potential
dc.titleInhibition of fatty acid synthesis aggravates brain injury, reduces blood-brain barrier integrity and impairs neurological recovery in a murine stroke model
dc.typeArticle

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