Lithium attenuates blood–brain barrier damage and brain edema following intracerebral hemorrhage via an endothelial Wnt/β‐catenin signaling‐dependent mechanism in mice

• Published in: CNS neuroscience & therapeutics Vol. 28; no. 6; pp. 862 - 872
• Main Authors: Song, Dengpan, Ji, Ya‐Bin, Huang, Xiao‐Wen, Ma, Yin‐Zhong, Fang, Cheng, Qiu, Lin‐Hui, Tan, Xi‐Xi, Chen, Yi‐Man, Wang, Sheng‐Nan, Chang, Junlei, Guo, Fuyou
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.06.2022; John Wiley and Sons Inc
• Subjects: Animals; Antibodies; beta Catenin - metabolism; Blood-brain barrier; Blood-Brain Barrier - metabolism; Brain; Brain Edema - drug therapy; Brain Edema - etiology; Brain Edema - metabolism; Brain injury; Catenin; Cerebral Hemorrhage - complications; Cerebral Hemorrhage - drug therapy; Cerebral Hemorrhage - metabolism; Collagen; Collagenase; Edema; Endothelium; Extravasation; Hematoma; Hematoma - metabolism; Hemorrhage; Immunoglobulin G; intracerebral hemorrhage; Laboratory animals; Lithium; Lithium - metabolism; Lithium - pharmacology; Lithium - therapeutic use; Mice; Mice, Knockout; Proteins; Rodents; Software; Special Issue; Statistical analysis; tight junction; Variance analysis; Volumetric analysis; Wnt protein; Wnt Signaling Pathway - physiology; Wnt/β‐catenin signaling; Wnt/β-catenin signaling; blood-brain barrier; intracerebral hemorrhage; lithium; tight junction
• ISSN: 1755-5930; 1755-5949
• DOI: 10.1111/cns.13832

Background 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. Methods 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. Results 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. Conclusion 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.