SUR1-TRPM4 channels, not KATP, mediate brain swelling following cerebral ischemia
SUR1-TRPM4 channels, not KATP, mediate brain swelling following cerebral ischemia
复制标题
DOI：
10.1016/j.neulet.2019.134729
复制
发表时间：
2020-01-23
影响因子：
2.5
通讯作者：
Simard, J. Marc
中科院分区：
文献类型：
--
作者：
Woo, Seung Kyoon;Tsymbalyuk, Natalia;Simard, J. Marc
背景资料：临床前和新出现的临床数据表明，格列本脲可减少脑缺血后的占位性水肿和脑肿胀。格列本脲是多种磺酰脲类受体（SUR）调节通道的强效抑制剂，包括K-ATP（SUR 1-KIR 6. 2、SUR 2A-KIR 6. 2、SUR 2B-KIR 6.2、SUR 2B-KIR 6.1）和SUR 1-TRPM 4。在这里，我们使用分子特异性寡脱氧核苷酸（ODNs），探讨各种SUR调节离子通道亚基在缺血后brain swelling.Methods的作用：局灶性脑缺血诱导成年雄性大鼠永久性大脑中动脉闭塞（pMCAo）。我们利用该模型研究了针对Abcc 8/SUR 1、Trpm 4/TRPM 4、Kcnj 8/KIR6.1和Kcnj 11/KIR6.2的反义ODNs（AS-ODNs）对大脑半球肿胀的影响，并以正义ODNs或乱序ODNs作为对照。我们使用基于抗体的福斯特共振能量转移结果：在联合对照组中，正义ODNs和乱序ODNs分别作用于pMCAo细胞后，均能引起较大的梗死体积（平均值+/- SD：57.4 +/-8.8%; n = 34），AS-ODN对梗死面积没有影响。在对照组中，半球肿胀为23.9 ± 4.1%（n = 34），并且肿胀与梗死体积线性相关（P < 0.02）。在给予抗Abcc 8/SUR 1或抗Trpm 4/TRPM 4 AS-ODN的组中，半球肿胀显著较少，分别为11.6 +/-3.9%和12.8 +/-5.8%（P < 0.0001），并且梗死体积和肿胀之间的关系减小且不显著。针对Kcnj 8/KIR6.1和Kcnj 11/KIR6.2的AS-ODN对半球肿胀没有显著影响（分别为23.3 +/-5.4%和22.9 +/-5.8%）。结论：脑缺血后脑肿胀与梗死体积无关。SUR 1-TRPM 4通道，而不是K-ATP，介导缺血后脑肿胀。
Background: 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.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 Forster 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 K-ATP, mediate post-ischemic brain swelling.