Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China.
Shenzhen Key Laboratory of Biomimetic Materials and Cellular Immunomodulation, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
CNS Neurosci Ther. 2022 Jun;28(6):862-872. doi: 10.1111/cns.13832. Epub 2022 Mar 28.
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 mm vs. 19.97 ± 3.20 mm 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.
血脑屏障（BBB）损伤导致的血管源性脑水肿使脑出血（ICH）的破坏性后果更加严重。尽管增强内皮细胞 Wnt/β-catenin 信号可以显著减轻动物的 BBB 破裂，但目前临床上还没有基于这种机制的药物。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。
我们评估了锂对胶原酶 IV 诱导的 ICH 小鼠模型中 BBB 的保护作用。此外，我们评估了锂对内皮细胞 Wnt7 共激活因子 Gpr124 缺失的小鼠中 Wnt/β-catenin 信号的作用和依赖性。
锂治疗（3mmol/kg）显著降低血肿体积（治疗组为 11.15±3.89mm，对照组为 19.97±3.20mm，p=0.0016），改善 ICH 后小鼠的神经功能。重要的是，锂显著增加了 BBB 的完整性，表现为脑水肿水平降低（p=0.0312）、伊文思蓝渗漏减少（p=0.0261）和血肿周围脑组织中血液 IgG 漏出减少（p=0.0009）。机制上，锂上调了小鼠内皮细胞 Wnt/β-catenin 信号的活性，增加了紧密连接蛋白（occludin、claudin-5 和 ZO-1）的水平。此外，内皮细胞 Gpr124 敲除小鼠中锂对脑损伤和 BBB 完整性的保护作用被消除，表明其对 BBB 功能的保护作用主要依赖于 Gpr124 介导的内皮细胞 Wnt/β-catenin 信号。
我们的研究结果表明，锂可能成为治疗 ICH 后 BBB 破裂和脑水肿的治疗候选药物。
