Lithium attenuates blood-brain barrier damage and brain edema following intracerebral hemorrhage via an endothelial Wnt/β-catenin signaling-dependent mechanism in mice.
Lithium attenuates blood-brain barrier damage and brain edema following intracerebral hemorrhage via an endothelial Wnt/β-catenin signaling-dependent mechanism in mice.
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DOI：
10.1111/cns.13832
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发表时间：
2022-06
影响因子：
5.5
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血脑屏障(BBB)损伤引起的血管源性脑水肿加重了脑出血(ICH)的破坏性后果。虽然内皮细胞Wnt/β-catenin信号的增强可以显著减轻动物的血脑屏障破坏，但临床上还没有基于这一机制的药物。锂是一种用于治疗双相情感障碍的药物，可以上调Wnt/β-Catenin信号。在IV型胶原酶诱导的小鼠脑出血模型中，我们评价了锂对血脑屏障的保护作用。此外，我们评估了锂对WNT/β-连环蛋白信号转导的影响和对WNT/GPR124内皮细胞缺失的小鼠的依赖性。锂治疗(3 mg/kg)可显著减少脑出血小鼠的血肿体积(11.15±33.89 mm3 vs 19.97±33.20 mm3，p=0.0016)，并改善脑出血后小鼠的神经功能状况。重要的是，锂显著增加了血脑屏障的完整性，其证据是脑水肿(p=0.0312)、伊文斯蓝渗漏(p=0.0261)和血免疫球蛋白渗入血肿周围脑组织(p=0.0009)的水平降低。在机制上，锂上调了小鼠内皮细胞Wnt/β-catenin信号的活性，并增加了紧密连接蛋白(occludin，claudin-5和zo-1)的水平。此外，锂对内皮GPR124基因敲除小鼠脑损伤和血脑屏障完整性的保护作用被取消，提示锂对血脑屏障功能的保护作用主要依赖于GPR124介导的内皮Wnt/β-catenin信号转导。我们的研究结果表明，锂可以作为治疗脑出血后血脑屏障破坏和脑水肿的候选药物。锂显著减少脑出血后小鼠的血肿量和改善神经预后，并增加血脑屏障的完整性，通过GPR124介导的内皮Wnt/β-catenin信号减少脑水肿、伊文斯蓝渗漏和血液免疫球蛋白外溢。锂可作为治疗脑出血后血脑屏障破坏和脑水肿的候选药物。
Vasogenic cerebral edema resulting from blood–brain barrier (BBB) damage aggravates the devastating consequences of intracerebral hemorrhage (ICH). Although augmentation of endothelial Wnt/β‐catenin signaling substantially alleviates BBB breakdown in animals, no agents based on this mechanism are clinically available. Lithium is a medication used to treat bipolar mood disorders and can upregulate Wnt/β‐catenin signaling. We evaluated the protective effect of lithium on the BBB in a mouse model of collagenase IV‐induced ICH. Furthermore, we assessed the effect and dependency of lithium on Wnt/β‐catenin signaling in mice with endothelial deletion of the Wnt7 coactivator Gpr124. Lithium treatment (3 mmol/kg) significantly decreased the hematoma volume (11.15 ± 3.89 mm3 vs. 19.97 ± 3.20 mm3 in vehicle controls, p = 0.0016) and improved the neurological outcomes of mice following ICH. Importantly, lithium significantly increased the BBB integrity, as evidenced by reductions in the levels of brain edema (p = 0.0312), Evans blue leakage (p = 0.0261), and blood IgG extravasation (p = 0.0009) into brain tissue around the hematoma. Mechanistically, lithium upregulated the activity of endothelial Wnt/β‐catenin signaling in mice and increased the levels of tight junction proteins (occludin, claudin‐5 and ZO‐1). Furthermore, the protective effect of lithium on cerebral damage and BBB integrity was abolished in endothelial Gpr124 knockout mice, suggesting that its protective effect on BBB function was mainly dependent on Gpr124‐mediated endothelial Wnt/β‐catenin signaling. Our findings indicate that lithium may serve as a therapeutic candidate for treating BBB breakdown and brain edema following ICH. Lithium significantly decreases hematoma volume and improved neurological outcomes of mice following intracerebral hemorrhage (ICH), and increases blood–brain barrier (BBB) integrity evidenced by reduction of brain edema, Evans blue leakage, and blood IgG extravasation via the Gpr124‐mediated endothelial Wnt/β‐catenin signaling. Lithium may serve as a therapeutic candidate for treating the BBB breakdown and brain edema following ICH.
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