GSK-3β as a target for protection against transient cerebral ischemia.
GSK-3β as a target for protection against transient cerebral ischemia.
复制标题
GSK-3 beta 作为预防短暂性脑缺血的靶标
DOI：
10.7150/ijms.17514
复制
发表时间：
2017
影响因子：
3.6
通讯作者：
Wang J
中科院分区：
文献类型：
--
作者：
Wang W;Li M;Wang Y;Wang Z;Zhang W;Guan F;Chen Q;Wang J
中风仍然是世界范围内导致死亡和残疾的主要原因。这一事实突显了寻找可以减少与中风相关的脑损伤的潜在药物靶点的必要性。我们最近发现一种糖原合成酶-3β(β)抑制剂可以减轻组织纤溶酶原激活剂诱导的永久性局灶性脑缺血后的出血性转化。在这里，我们研究了抑制葛兰素史克-3β是否减轻早期缺血-再灌注性卒中损伤，并探讨了其潜在的作用机制。采用大鼠大脑中动脉闭塞(MCAO)模型模拟短暂性脑缺血。MCAO后3.5h，脑血流量恢复，二甲基亚砜(溶剂，1%生理盐水)或GSK-3β抑制剂TWS119(30 mg/kg)腹腔注射。MCAO后24小时处死动物。与赋形剂组相比，TWS119治疗可减少神经功能缺失、脑水肿、脑梗塞体积和血脑屏障通透性。TWS119还能增加β-连环蛋白和闭锁带-1的蛋白表达，降低β-连环蛋白的磷酸化，抑制β的表达。这些结果表明，抑制GSK-3β可以保护血脑屏障，减轻早期脑缺血再灌注损伤。这种保护作用可能与Wnt/β-连环蛋白信号通路的早期激活有关。
Stroke remains the leading cause of death and disability worldwide. This fact highlights the need to search for potential drug targets that can reduce stroke-related brain damage. We showed recently that a glycogen synthase kinase-3β (GSK-3β) inhibitor attenuates tissue plasminogen activator-induced hemorrhagic transformation after permanent focal cerebral ischemia. Here, we examined whether GSK-3β inhibition mitigates early ischemia-reperfusion stroke injury and investigated its potential mechanism of action. We used the rat middle cerebral artery occlusion (MCAO) model to mimic transient cerebral ischemia. At 3.5 h after MCAO, cerebral blood flow was restored, and rats were administered DMSO (vehicle, 1% in saline) or GSK-3β inhibitor TWS119 (30 mg/kg) by intraperitoneal injection. Animals were sacrificed 24 h after MCAO. TWS119 treatment reduced neurologic deficits, brain edema, infarct volume, and blood-brain barrier permeability compared with those in the vehicle group. TWS119 treatment also increased the protein expression of β-catenin and zonula occludens-1 but decreased β-catenin phosphorylation while suppressing the expression of GSK-3β. These results indicate that GSK-3β inhibition protects the blood-brain barrier and attenuates early ischemia-reperfusion stroke injury. This protection may be related to early activation of the Wnt/β-catenin signaling pathway.