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dc.contributor.authorWoo, S.K.
dc.contributor.authorTsymbalyuk, N.
dc.contributor.authorTsymbalyuk, O.
dc.contributor.authorIvanova, S.
dc.contributor.authorGerzanich, V.
dc.contributor.authorSimard, J.M.
dc.date.accessioned2020-02-04T16:19:38Z
dc.date.available2020-02-04T16:19:38Z
dc.date.issued2020
dc.identifier.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85078390913&doi=10.1016%2fj.neulet.2019.134729&partnerID=40&md5=8ed65b3920f0073f4b36ade2bf405a42
dc.identifier.urihttp://hdl.handle.net/10713/11654
dc.description.abstractBACKGROUND: Preclinical and emerging clinical data show that glibenclamide reduces space occupying edema and brain swelling following cerebral ischemia. Glibenclamide is a potent inhibitor of numerous sulfonylurea receptor (SUR)-regulated channels, including KATP (SUR1-KIR6.2, SUR2A-KIR6.2, SUR2B-KIR6.2, SUR2B-KIR6.1) and SUR1-TRPM4. Here, we used molecularly specific oligodeoxynucleotides (ODNs) to investigate the role of various SUR-regulated ion channel subunits in post-ischemic brain swelling. METHODS: Focal cerebral ischemia was induced in adult male rats by permanent middle cerebral artery occlusion (pMCAo). We used this model to study the effects of antisense-ODNs (AS-ODNs) directed against Abcc8/SUR1, Trpm4/TRPM4, Kcnj8/KIR6.1 and Kcnj11/KIR6.2 on hemispheric swelling, with sense or scrambled ODNs used as controls. We used antibody-based Förster resonance energy transfer (immuno-FRET) and co-immunoprecipitation to study the co-assembly of SUR1-TRPM4 heteromers. RESULTS: In the combined control groups administered sense or scrambled ODNs, pMCAo resulted in uniformly large infarct volumes (mean ± SD: 57.4 ± 8.8 %; n = 34) at 24 h after onset of ischemia, with no effect of AS-ODNs on infarct size. In controls, hemispheric swelling was 23.9 ± 4.1 % (n = 34), and swelling was linearly related to infarct volume (P < 0.02). In the groups administered anti-Abcc8/SUR1 or anti-Trpm4/TRPM4 AS-ODN, hemispheric swelling was significantly less, 11.6 ± 3.9 % and 12.8 ± 5.8 % respectively (P < 0.0001), and the relationship between infarct volume and swelling was reduced and not significant. AS-ODNs directed against Kcnj8/KIR6.1 and Kcnj11/KIR6.2 had no significant effect on hemispheric swelling (23.3 ± 5.4 % and 22.9 ± 5.8 % respectively). Post-ischemic tissues showed co-assembly of SUR1-TRPM4 heteromers. CONCLUSIONS: Post-ischemic hemispheric swelling can be decoupled from infarct volume. SUR1-TRPM4 channels, not KATP, mediate post-ischemic brain swelling. Copyright 2019 The Author(s).en_US
dc.description.sponsorshipDepartment 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);NINDS (R01NS061934; R01NS107262)en_US
dc.description.urihttps://doi.org/10.1016/j.neulet.2019.134729en_US
dc.language.isoen_USen_US
dc.publisherElsevieren_US
dc.relation.ispartofNeuroscience letters
dc.subjectCerebral edemaen_US
dc.subjectCerebral ischemiaen_US
dc.subjectHemispheric swellingen_US
dc.subjectK(ATP) channelen_US
dc.subjectSulfonylurea receptor 1 (SUR1)en_US
dc.subjectSUR1-TRPM4 channelen_US
dc.subjectTransient receptor potential melastatin 4 (TRPM4)en_US
dc.titleSUR1-TRPM4 channels, not K(ATP), mediate brain swelling following cerebral ischemiaen_US
dc.typeArticleen_US
dc.identifier.doi10.1016/j.neulet.2019.134729
dc.identifier.pmid31899311


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