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dc.contributor.authorManrique-Castano, Daniel
dc.contributor.authorSardari, Maryam
dc.contributor.authorde Carvalho, Tayana Silva
dc.contributor.authorDoeppner, Thorsten R
dc.contributor.authorPopa-Wagner, Aurel
dc.contributor.authorKleinschnitz, Christoph
dc.contributor.authorChan, Andrew
dc.contributor.authorHermann, Dirk M
dc.date.accessioned2019-12-13T04:51:16Z
dc.date.available2019-12-13T04:51:16Z
dc.date.issued2019
dc.identifier.issn1662-5102en_US
dc.identifier.doi10.3389/fncel.2019.00412en_US
dc.identifier.urihttp://hdl.handle.net/10072/389788
dc.description.abstractATP-binding cassette (ABC) transporters prevent the access of pharmacological compounds to the ischemic brain, thereby impeding the efficacy of stroke therapies. ABC transporters can be deactivated by selective inhibitors, which potently increase the brain accumulation of drugs. Concerns have been raised that long-term ABC transporter deactivation may promote neuronal degeneration and, under conditions of ischemic stroke, compromise neurological recovery. To elucidate this issue, we exposed male C57BL/6 mice to transient intraluminal middle cerebral artery occlusion (MCAO) and examined the effects of the selective ABCB1 inhibitor tariquidar (8 mg/kg/day) or ABCC1 inhibitor MK-571 (10 mg/kg/day), which were administered alone or in combination with each other over up to 28 days, on neurological recovery and brain injury. Mice were sacrificed after 14, 28, or 56 days. The Clark score, RotaRod, tight rope, and open field tests revealed reproducible motor-coordination deficits in mice exposed to intraluminal MCAO, which were not influenced by ABCB1, ABCC1, or combined ABCB1 and ABCC1 deactivation. Brain volume, striatum volume, and corpus callosum thickness were not altered by ABCB1, ABCC1 or ABCB1, and ABCC1 inhibitors. Similarly, neuronal survival and reactive astrogliosis, evaluated by NeuN and GFAP immunohistochemistry in the ischemic striatum, were unchanged. Iba1 immunohistochemistry revealed no changes of the overall density of activated microglia in the ischemic striatum of ABC transporter inhibitor treated mice, but subtle changes of microglial morphology, that is, reduced microglial cell volume by ABCB1 deactivation after 14 and 28 days and reduced microglial ramification by ABCB1, ABCC1 and combined ABCB1 and ABCC1 deactivation after 56 days. Endogenous neurogenesis, assessed by BrdU incorporation analysis, was not influenced by ABCB1, ABCC1 or combined ABCB1 and ABCC1 deactivation. Taken together, this study could not detect any exacerbation of neurological deficits or brain injury after long-term ABC transporter deactivation in this preclinical stroke model.en_US
dc.description.peerreviewedYesen_US
dc.languageEnglishen_US
dc.publisherFrontiers Research Foundationen_US
dc.publisher.placeSwitzerland
dc.relation.ispartofpagefrom412: 1en_US
dc.relation.ispartofpageto412: 9en_US
dc.relation.ispartofjournalFrontiers in Cellular Neuroscienceen_US
dc.relation.ispartofvolume13en_US
dc.subject.fieldofresearchNeurosciencesen_US
dc.subject.fieldofresearchBiochemistry and Cell Biologyen_US
dc.subject.fieldofresearchcode1109en_US
dc.subject.fieldofresearchcode0601en_US
dc.subject.keywordsMULTIDRUG-RESISTANCEen_US
dc.subject.keywordsGLYCOPROTEINen_US
dc.subject.keywordsINHIBITIONen_US
dc.subject.keywordsScience & Technologyen_US
dc.subject.keywordsLife Sciences & Biomedicineen_US
dc.titleDeactivation of ATP-Binding Cassette Transporters ABCB1 and ABCC1 Does Not Influence Post-ischemic Neurological Deficits, Secondary Neurodegeneration and Neurogenesis, but Induces Subtle Microglial Morphological Changesen_US
dc.typeJournal articleen_US
dc.type.descriptionC1 - Articlesen_US
dcterms.bibliographicCitationManrique-Castano, D; Sardari, M; de Carvalho, TS; Doeppner, TR; Popa-Wagner, A; Kleinschnitz, C; Chan, A; Hermann, DM, Deactivation of ATP-Binding Cassette Transporters ABCB1 and ABCC1 Does Not Influence Post-ischemic Neurological Deficits, Secondary Neurodegeneration and Neurogenesis, but Induces Subtle Microglial Morphological Changes, Frontiers in Cellular Neuroscience, 2019, 13, pp. 412: 1-412: 9en_US
dcterms.dateAccepted2019-08-27
dcterms.licensehttp://creativecommons.org/licenses/by/4.0/en_US
dc.date.updated2019-12-13T04:12:40Z
dc.description.versionPublisheden_US
gro.rights.copyright© 2019 Manrique-Castano, Sardari, Silva de Carvalho, Doeppner, Popa-Wagner, Kleinschnitz, Chan and Hermann. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.en_US
gro.hasfulltextFull Text
gro.griffith.authorPopa-Wagner, Aurel


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