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Although augmentation of endothelial Wnt\/\u03b2\u2010catenin 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\/\u03b2\u2010catenin signaling.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We evaluated the protective effect of lithium on the BBB in a mouse model of collagenase IV\u2010induced ICH. Furthermore, we assessed the effect and dependency of lithium on Wnt\/\u03b2\u2010catenin signaling in mice with endothelial deletion of the Wnt7 coactivator <jats:italic>Gpr124<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Lithium treatment (3\u00a0mmol\/kg) significantly decreased the hematoma volume (11.15\u00a0\u00b1\u00a03.89\u00a0mm<jats:sup>3<\/jats:sup> vs. 19.97\u00a0\u00b1\u00a03.20\u00a0mm<jats:sup>3<\/jats:sup> in vehicle controls, <jats:italic>p<\/jats:italic>\u00a0=\u00a00.0016) 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 (<jats:italic>p<\/jats:italic>\u00a0=\u00a00.0312), Evans blue leakage (<jats:italic>p<\/jats:italic>\u00a0=\u00a00.0261), and blood IgG extravasation (<jats:italic>p<\/jats:italic>\u00a0=\u00a00.0009) into brain tissue around the hematoma. Mechanistically, lithium upregulated the activity of endothelial Wnt\/\u03b2\u2010catenin signaling in mice and increased the levels of tight junction proteins (occludin, claudin\u20105 and ZO\u20101). Furthermore, the protective effect of lithium on cerebral damage and BBB integrity was abolished in endothelial <jats:italic>Gpr124<\/jats:italic>\u00a0knockout mice, suggesting that its protective effect on BBB function was mainly dependent on Gpr124\u2010mediated endothelial Wnt\/\u03b2\u2010catenin signaling.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our findings indicate that lithium may serve as a therapeutic candidate for treating BBB breakdown and brain edema following ICH.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cns.13832","type":"journal-article","created":{"date-parts":[[2022,3,28]],"date-time":"2022-03-28T07:20:10Z","timestamp":1648452010000},"page":"862-872","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Lithium attenuates blood\u2013brain barrier damage and brain edema following intracerebral hemorrhage via an endothelial Wnt\/\u03b2\u2010catenin signaling\u2010dependent mechanism in mice"],"prefix":"10.1111","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5240-7601","authenticated-orcid":false,"given":"Dengpan","family":"Song","sequence":"first","affiliation":[{"name":"Department of Neurosurgery The First Affiliated Hospital of Zhengzhou University Zhengzhou University  Zhengzhou China"},{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ya\u2010Bin","family":"Ji","sequence":"additional","affiliation":[{"name":"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"},{"name":"Department of Neurology Nanfang Hospital Southern Medical 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