Lithium alleviates blood-brain barrier breakdown after cerebral ischemia and reperfusion by upregulating endothelial Wnt/β-catenin signaling in mice
| Autor: | Xiao-Wen Huang, Yin-Zhong Ma, Cheng Fang, Shengnan Wang, Qiang Gao, Yong-Xian Cheng, Ya-Bin Ji, Xi-Xi Tan, Lin-Hui Qiu, Fu-You Guo, Junlei Chang |
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| Rok vydání: | 2021 |
| Předmět: |
Male
0301 basic medicine Lithium (medication) Ischemia Mice Transgenic Pharmacology Blood–brain barrier Brain Ischemia Mice 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Adjuvants Immunologic Downregulation and upregulation medicine Animals Wnt Signaling Pathway beta Catenin Mice Knockout Tight junction business.industry Wnt signaling pathway Endothelial Cells medicine.disease Up-Regulation Mice Inbred C57BL 030104 developmental biology medicine.anatomical_structure Mood disorders Blood-Brain Barrier Reperfusion Injury Lithium Chloride business Reperfusion injury 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Neuropharmacology. 186:108474 |
| ISSN: | 0028-3908 |
| DOI: | 10.1016/j.neuropharm.2021.108474 |
| Popis: | Although upregulation of endothelial Wnt/β-catenin signaling may be used to treat blood-brain barrier (BBB) breakdown caused by cerebral ischemia/reperfusion injury, no agents based on this mechanism are available clinically. Lithium, a medication used for treating bipolar mood disorders, upregulates Wnt/β-catenin signaling, but whether lithium alleviates BBB breakdown after ischemic stroke by upregulating endothelial Wnt/β-catenin signaling is unclear. Here, we evaluated the BBB-protective effect of lithium in adult mice with 1-h middle cerebral artery occlusion and 48-h reperfusion (MCAO/R) by determining neurological outcomes, BBB function and related molecular components. Furthermore, we assessed the effect and dependence of lithium on Wnt/β-catenin signaling in brain microvascular endothelial cells in cell culture and in mice with conditional endothelial knockout of Wnt7 co-receptor Gpr124. Our data show that lithium treatment (3 mmol/kg) significantly decreased infarct volume (34.1 ± 1.8% versus 58.3 ± 2.8% in vehicle controls, P 0.0001) and improved neurological outcomes of mice following MCAO/R. Importantly, lithium significantly increased BBB integrity shown by reduction of Evans blue leakage (by 45.7%, P = 0.0064) and blood IgG extravasation (by 65.8%, P 0.0001) into infarcted brain tissue. Mechanistically, lithium upregulated the activity of endothelial Wnt/β-catenin signaling in vivo and in vitro, increased the protein levels of tight junctions (Claudin-5 and ZO-1), and reduced MMP-9 expression. Furthermore, the protective effect of lithium on cerebral damage and BBB integrity was abolished in endothelial Gpr124 knockout mice, indicating the protection of lithium on BBB was mainly dependent on the Gpr124-mediated endothelial Wnt/β-catenin signaling. Taken together, our findings indicate that lithium may serve as a therapeutic candidate for treating the BBB breakdown in the early stage of ischemic stroke following reperfusion therapy. |
| Databáze: | OpenAIRE |
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