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dc.contributor.authorGerzanich, V.
dc.contributor.authorStokum, J.A.
dc.contributor.authorIvanova, S.
dc.date.accessioned2019-09-13T16:42:05Z
dc.date.available2019-09-13T16:42:05Z
dc.date.issued2019
dc.identifier.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85063257865&doi=10.1089%2fneu.2018.5986&partnerID=40&md5=d07092345853107c10fadd75aed76d53
dc.identifier.urihttp://hdl.handle.net/10713/10768
dc.description.abstractIn severe traumatic brain injury (TBI), contusions often are worsened by contusion expansion or hemorrhagic progression of contusion (HPC), which may double the original contusion volume and worsen outcome. In humans and rodents with contusion-TBI, sulfonylurea receptor 1 (SUR1) is upregulated in microvessels and astrocytes, and in rodent models, blockade of SUR1 with glibenclamide reduces HPC. SUR1 does not function by itself, but must co-assemble with either KIR6.2 or transient receptor potential cation channel subfamily M member 4 (TRPM4) to form KATP (SUR1-KIR6.2) or SUR1-TRPM4 channels, with the two having opposite effects on membrane potential. Both KIR6.2 and TRPM4 are reportedly upregulated in TBI, especially in astrocytes, but the identity and function of SUR1-regulated channels post-TBI is unknown. Here, we analyzed human and rat brain tissues after contusion-TBI to characterize SUR1, TRPM4, and KIR6.2 expression, and in the rat model, to examine the effects on HPC of inhibiting expression of the three subunits using intravenous antisense oligodeoxynucleotides (AS-ODN). Glial fibrillary acidic protein (GFAP) immunoreactivity was used to operationally define core versus penumbral tissues. In humans and rats, GFAP-negative core tissues contained microvessels that expressed SUR1 and TRPM4, whereas GFAP-positive penumbral tissues contained astrocytes that expressed all three subunits. Förster resonance energy transfer imaging demonstrated SUR1-TRPM4 heteromers in endothelium, and SUR1-TRPM4 and SUR1-KIR6.2 heteromers in astrocytes. In rats, glibenclamide as well as AS-ODN targeting SUR1 and TRPM4, but not KIR6.2, reduced HPC at 24 h post-TBI. Our findings demonstrate upregulation of SUR1-TRPM4 and KATP after contusion-TBI, identify SUR1-TRPM4 as the primary molecular mechanism that accounts for HPC, and indicate that SUR1-TRPM4 is a crucial target of glibenclamide. Copyright 2018 Volodymyr Gerzanich et al. Published by Mary Ann Liebert, Inc.en_US
dc.description.sponsorshipJ.M.S is supported by grants from the Department of Veterans Affairs (I01BX002889), the Department of Defense (SCI170199), the National Heart, Lung and Blood Institute (R01HL082517) and the National Institute of Neurological Disorders and Stroke (NINDS) (R01NS060801; R01NS102589; R01NS105633); V.G. is supported by a grant from NINDS (NS061934).en_US
dc.description.urihttps://doi.org/10.1089/neu.2018.5986en_US
dc.language.isoen-USen_US
dc.publisherMary Ann Liebert Inc.en_US
dc.relation.ispartofJournal of Neurotrauma
dc.subject.meshBrain Injuries, Traumaticen_US
dc.subject.meshCerebral Hemorrhage, Traumatic--physiopathologyen_US
dc.titleSulfonylurea receptor 1, transient receptor potential cation channel subfamily M member 4, and KIR6.2:Role in hemorrhagic progression of contusionen_US
dc.typeArticleen_US
dc.identifier.doi10.1089/neu.2018.5986
dc.identifier.pmid30160201


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