Lithium alleviates blood-brain barrier breakdown after cerebral ischemia and reperfusion by upregulating endothelial Wnt/β-catenin signaling in mice
Lithium alleviates blood-brain barrier breakdown after cerebral ischemia and reperfusion by upregulating endothelial Wnt/β-catenin signaling in mice
复制标题
锂通过上调小鼠内皮 Wnt/β-连环蛋白信号传导来减轻脑缺血和再灌注后血脑屏障的破坏。
DOI：
10.1016/j.neuropharm.2021.108474
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发表时间：
2021-02-06
影响因子：
4.7
通讯作者：
Chang, Junlei
中科院分区：
文献类型：
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作者：
Ji, Ya-Bin;Gao, Qiang;Chang, Junlei
尽管内皮Wnt/β-连环蛋白信号传导的上调可用于治疗由脑缺血/再灌注损伤引起的血脑屏障（BBB）破坏，但临床上没有基于该机制的药物。锂，一种用于治疗双相情感障碍的药物，上调Wnt/β-连环蛋白信号传导，但锂是否通过上调内皮Wnt/β-连环蛋白信号传导来抑制缺血性卒中后的BBB破坏尚不清楚。在此，我们通过测定神经学结果、血脑屏障功能和相关分子成分，评估了锂对大脑中动脉闭塞1小时再灌注48小时（MCAO/R）成年小鼠血脑屏障的保护作用。此外，我们评估了锂对细胞培养物中的脑微血管内皮细胞中的Wnt/β-连环蛋白信号传导的影响和依赖性，以及对Wnt 7共受体Gpr 124的条件性内皮敲除小鼠的影响和依赖性。我们的数据显示，锂治疗（3 mmol/kg）显著降低了MCAO/R后小鼠的梗死体积（34.1 +/- 1.8% vs 58.3 +/- 2.8%，P < 0.0001），并改善了神经功能结局。重要的是，锂显著增加了BBB的完整性，表现为伊文思蓝渗漏（45.7%，P = 0.0064）和血液IgG外渗（65.8%，P < 0.0001）到梗死脑组织中的减少。从机制上讲，锂在体内和体外上调内皮Wnt/β-连环蛋白信号传导的活性，增加紧密连接（Claudin-5和ZO-1）的蛋白水平，并降低MMP-9的表达。此外，锂对内皮Gpr 124基因敲除小鼠脑损伤和血脑屏障完整性的保护作用被消除，表明锂对血脑屏障的保护作用主要依赖于Gpr 124介导的内皮Wnt/β-catenin信号转导。综上所述，我们的研究结果表明，锂可以作为治疗缺血性卒中再灌注治疗后早期BBB崩溃的治疗候选药物。
Although upregulation of endothelial Wnt/beta-catenin signaling may be used to treat blood-brain barrier (BBB) breakdown caused by cerebral ischemia/reperfusion injury, no agents based on this mechanism are available clinically. Lithium, a medication used for treating bipolar mood disorders, upregulates Wnt/beta-catenin signaling, but whether lithium alleviates BBB breakdown after ischemic stroke by upregulating endothelial Wnt/beta-catenin signaling is unclear. Here, we evaluated the BBB-protective effect of lithium in adult mice with 1-h middle ce-rebral artery occlusion and 48-h reperfusion (MCAO/R) by determining neurological outcomes, BBB function and related molecular components. Furthermore, we assessed the effect and dependence of lithium on Wnt/beta-catenin signaling in brain microvascular endothelial cells in cell culture and in mice with conditional endothelial knockout of Wnt7 co-receptor Gpr124. Our data show that lithium treatment (3 mmol/kg) significantly decreased infarct volume (34.1 +/- 1.8% versus 58.3 +/- 2.8% in vehicle controls, P < 0.0001) and improved neurological outcomes of mice following MCAO/R. Importantly, lithium significantly increased BBB integrity shown by reduction of Evans blue leakage (by 45.7%, P = 0.0064) and blood IgG extravasation (by 65.8%, P < 0.0001) into infarcted brain tissue. Mechanistically, lithium upregulated the activity of endothelial Wnt/beta-catenin signaling in vivo and in vitro, increased the protein levels of tight junctions (Claudin-5 and ZO-1), and reduced MMP-9 expression. Furthermore, the protective effect of lithium on cerebral damage and BBB integrity was abolished in endothelial Gpr124 knockout mice, indicating the protection of lithium on BBB was mainly dependent on the Gpr124-mediated endothelial Wnt/beta -catenin signaling. Taken together, our findings indicate that lithium may serve as a therapeutic candidate for treating the BBB breakdown in the early stage of ischemic stroke following reperfusion therapy.