SUR1-TRPM4 channels, not KATP, mediate brain swelling following cerebral ischemia

Abstract

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 K ATP (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. 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 antibodybased Förster resonance energy transfer (immuno-FRET) and co-immunoprecipitation to study the co-assembly of SUR1-TRPM4 heteromers. 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 hours 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. Post-ischemic hemispheric swelling can be decoupled from infarct volume. SUR1-TRPM4 channels, not K ATP , mediate post-ischemic brain swelling.