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

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 mech...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9062576/
https://www.ncbi.nlm.nih.gov/pubmed/35343071
http://dx.doi.org/10.1111/cns.13832
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author 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
author_facet 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
author_sort Song, Dengpan
collection PubMed
description 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 mm(3) vs. 19.97 ± 3.20 mm(3) 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.
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spelling pubmed-90625762022-05-03 Lithium attenuates blood–brain barrier damage and brain edema following intracerebral hemorrhage via an endothelial Wnt/β‐catenin signaling‐dependent mechanism in mice 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 CNS Neurosci Ther Special Issue Article 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 mm(3) vs. 19.97 ± 3.20 mm(3) 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. John Wiley and Sons Inc. 2022-03-28 /pmc/articles/PMC9062576/ /pubmed/35343071 http://dx.doi.org/10.1111/cns.13832 Text en © 2022 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Special Issue Article
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
Lithium attenuates blood–brain barrier damage and brain edema following intracerebral hemorrhage via an endothelial Wnt/β‐catenin signaling‐dependent mechanism in mice
title Lithium attenuates blood–brain barrier damage and brain edema following intracerebral hemorrhage via an endothelial Wnt/β‐catenin signaling‐dependent mechanism in mice
title_full Lithium attenuates blood–brain barrier damage and brain edema following intracerebral hemorrhage via an endothelial Wnt/β‐catenin signaling‐dependent mechanism in mice
title_fullStr Lithium attenuates blood–brain barrier damage and brain edema following intracerebral hemorrhage via an endothelial Wnt/β‐catenin signaling‐dependent mechanism in mice
title_full_unstemmed Lithium attenuates blood–brain barrier damage and brain edema following intracerebral hemorrhage via an endothelial Wnt/β‐catenin signaling‐dependent mechanism in mice
title_short Lithium attenuates blood–brain barrier damage and brain edema following intracerebral hemorrhage via an endothelial Wnt/β‐catenin signaling‐dependent mechanism in mice
title_sort lithium attenuates blood–brain barrier damage and brain edema following intracerebral hemorrhage via an endothelial wnt/β‐catenin signaling‐dependent mechanism in mice
topic Special Issue Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9062576/
https://www.ncbi.nlm.nih.gov/pubmed/35343071
http://dx.doi.org/10.1111/cns.13832
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