The glucagon-like peptide-1 receptor agonist exendin-4 ameliorates warfarin-associated hemorrhagic transformation after cerebral ischemia.
The glucagon-like peptide-1 receptor agonist exendin-4 ameliorates warfarin-associated hemorrhagic transformation after cerebral ischemia.
复制标题
胰高血糖素样肽 1 受体激动剂 exendin-4 可改善脑缺血后华法林相关的出血性转化。
DOI：
10.1186/s12974-016-0661-0
复制
发表时间：
2016-08-26
影响因子：
9.3
通讯作者：
Cui M
中科院分区：
文献类型：
--
作者：
Chen F;Wang W;Ding H;Yang Q;Dong Q;Cui M
BackgroundAs the number of patients with cardioembolic ischemic stroke is predicted to be double by 2030, increased burden of warfarin-associated hemorrhagic transformation (HT) after cerebral ischemia is an expected consequence. However, thus far, no effective treatment strategy is available for HT prevention in routine clinical practice. While the glucagon-like peptide-1 receptor (GLP-1R) agonist exendin-4 (Ex-4) is known to protect against oxidative stress and neuronal cell death caused by ischemic brain damage, its effect on preventing warfarin-associated HT after cerebral ischemia is yet unknown. Therefore, we hypothesized that Ex-4 would stabilize the blood-brain barrier (BBB) and suppress neuroinflammation through PI3K-Akt-induced inhibition of glycogen synthase kinase-3β (GSK-3β) after warfarin-associated HT post-cerebral ischemia.MethodsWe used male C57BL/6 mice for all experiments. A 5-mg warfarin sodium tablet was dissolved in animals’ drinking water (effective warfarin uptake 0.04 mg (2 mg/kg) per mouse). The mice were fed for 0, 6, 12, and 24 h with ad libitum access to the treated water. To study the effects of Ex-4, temporary middle cerebral artery occlusion (MCAO) was performed. Then, either Ex-4 (10 mg/kg) or saline was injected through the tail vein, and in the Ex-4 + wortmannin group, PI3K inhibitor wortmannin was intravenously injected, after reperfusion. The infarct volume, neurological deficits, and integrity of the BBB were assessed 72 h post MCAO. One- or two-way ANOVA was used to test the difference between means followed by Newman–Keuls post hoc testing for pair-wise comparison.ResultsWe observed that Ex-4 ameliorated warfarin-associated HT and preserved the integrity of the BBB after cerebral ischemia through the PI3K/Akt/GSK-3β pathway. Furthermore, Ex-4 suppressed oxidative DNA damage and lipid peroxidation, attenuated pro-inflammatory cytokine expression levels, and suppressed microglial activation and neutrophil infiltration in warfarin-associated HT post-cerebral ischemia. However, these effects were totally abolished in the mice treated with Ex-4 + the PI3K inhibitor—wortmannin. The PI3K/Akt-GSK-3β signaling pathway appeared to contribute to the protection afforded by Ex-4 in the warfarin-associated HT model.ConclusionsGLP-1 administration could reduce warfarin-associated HT in mice. This beneficial effect of GLP-1 is associated with attenuating neuroinflammation and BBB disruption by inactivating GSK-3β through the PI3K/Akt pathway.
登录
查看更多内容
影响因子：
4.6
作者：
Leis, H;Segrelles, C;Paramio, JM
通讯作者：
Paramio, JM
影响因子：
16.8
作者：
Fukao, T;Koyasu, S
通讯作者：
Koyasu, S
影响因子：
4.8
作者：
Guturi, Kiran Kumar Naidu;Mandal, Tapashi;Ghosh, Mrinal K.
通讯作者：
Ghosh, Mrinal K.
Wnt/β-catenin信号传导控制血脑屏障的发展。
影响因子：
7.8
作者：
Liebner, Stefan;Corada, Monica;Bangsow, Thorsten;Babbage, Jane;Taddei, Andrea;Czupalla, Cathrin J.;Reis, Marco;Felici, Angelina;Wolburg, Hartwig;Fruttiger, Marcus;Taketo, Makoto M.;von Melchner, Harald;Plate, Karl Heinz;Gerhardt, Holger;Dejana, Elisabetta
通讯作者：
Dejana, Elisabetta
影响因子：
2.6
作者：
Lemiere, S;Cossu-Leguille, C;Vasseur, P
通讯作者：
Vasseur, P