RhoA/ROCK-2 Pathway Inhibition and Tight Junction Protein Upregulation by Catalpol Suppresses Lipopolysaccaride-Induced Disruption of Blood-Brain Barrier Permeability
Lipopolysaccaride (LPS) directly or indirectly injures brain microvascular endothelial cells (BMECs) and damages the intercellular tight junction that gives rise to altered blood-brain barrier (BBB) permeability. Catalpol plays a protective role in LPS-induced injury, but whether catalpol protects a...
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MDPI AG
2018-09-01
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| Series: | Molecules |
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| Online Access: | http://www.mdpi.com/1420-3049/23/9/2371 |
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| author | Shan Feng Li Zou Hongjin Wang Ran He Ke Liu Huifeng Zhu |
| author_facet | Shan Feng Li Zou Hongjin Wang Ran He Ke Liu Huifeng Zhu |
| author_sort | Shan Feng |
| collection | DOAJ |
| description | Lipopolysaccaride (LPS) directly or indirectly injures brain microvascular endothelial cells (BMECs) and damages the intercellular tight junction that gives rise to altered blood-brain barrier (BBB) permeability. Catalpol plays a protective role in LPS-induced injury, but whether catalpol protects against LPS-caused damage of BBB permeability and the underlying mechanism remain to be delineated. Prophylactic protection with catalpol (5 mg/kg, i.v.) consecutively for three days reversed the LPS-induced damage of BBB by decreased Evans Blue (EB) leakage and restored tight junctions in C57 mice. Besides, catalpol co-administrated with LPS increased BMECs survival, decreased their endothelin-1, TNF-Α and IL-6 secretion, improved transmembrane electrical resistance in a time-dependent manner, and in addition increased the fluorescein sodium permeability coefficient of BMECs. Also, transmission electron microscopy showed catalpol protective effects on tight junctions. Fluorescence staining displayed that catalpol reversed the rearrangement of the cytoskeleton protein F-actin and upregulated the tight junction protein of claudin-5 and ZO-1, which have been further demonstrated by the mRNA and protein expression levels of ZO-1, ZO-2, ZO-3, claudin-5, and occludin. Moreover, catalpol concurrently downregulated the mRNA and protein levels of RhoA, and ROCK2, the critical proteins in the RhoA/ROCK2 signaling pathway. This study thus indicated that catalpol, via inhibition of the RhoA/ROCK2 signaling pathway, reverses the disaggregation of cytoskeleton actin in BMECs and prevents down-regulation of junctional proteins, such as claudin-5, occludin, and ZO-1, and decreases endothelin-1 and inflammatory cytokine secretion, eventually alleviating the increase in LPS-induced BBB permeability. |
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| spelling | doaj.art-b7acd0e6fdb54734b76edf37783605e92022-12-21T17:32:10ZengMDPI AGMolecules1420-30492018-09-01239237110.3390/molecules23092371molecules23092371RhoA/ROCK-2 Pathway Inhibition and Tight Junction Protein Upregulation by Catalpol Suppresses Lipopolysaccaride-Induced Disruption of Blood-Brain Barrier PermeabilityShan Feng0Li Zou1Hongjin Wang2Ran He3Ke Liu4Huifeng Zhu5College of Pharmaceutical Sciences and Chinese Medicine, Southwest University, 2# Tiansheng Road, Beibei District, Chongqing 400715, ChinaCollege of Pharmaceutical Sciences and Chinese Medicine, Southwest University, 2# Tiansheng Road, Beibei District, Chongqing 400715, ChinaCollege of Pharmaceutical Sciences and Chinese Medicine, Southwest University, 2# Tiansheng Road, Beibei District, Chongqing 400715, ChinaCollege of Pharmaceutical Sciences and Chinese Medicine, Southwest University, 2# Tiansheng Road, Beibei District, Chongqing 400715, ChinaCollege of Pharmaceutical Sciences and Chinese Medicine, Southwest University, 2# Tiansheng Road, Beibei District, Chongqing 400715, ChinaCollege of Pharmaceutical Sciences and Chinese Medicine, Southwest University, 2# Tiansheng Road, Beibei District, Chongqing 400715, ChinaLipopolysaccaride (LPS) directly or indirectly injures brain microvascular endothelial cells (BMECs) and damages the intercellular tight junction that gives rise to altered blood-brain barrier (BBB) permeability. Catalpol plays a protective role in LPS-induced injury, but whether catalpol protects against LPS-caused damage of BBB permeability and the underlying mechanism remain to be delineated. Prophylactic protection with catalpol (5 mg/kg, i.v.) consecutively for three days reversed the LPS-induced damage of BBB by decreased Evans Blue (EB) leakage and restored tight junctions in C57 mice. Besides, catalpol co-administrated with LPS increased BMECs survival, decreased their endothelin-1, TNF-Α and IL-6 secretion, improved transmembrane electrical resistance in a time-dependent manner, and in addition increased the fluorescein sodium permeability coefficient of BMECs. Also, transmission electron microscopy showed catalpol protective effects on tight junctions. Fluorescence staining displayed that catalpol reversed the rearrangement of the cytoskeleton protein F-actin and upregulated the tight junction protein of claudin-5 and ZO-1, which have been further demonstrated by the mRNA and protein expression levels of ZO-1, ZO-2, ZO-3, claudin-5, and occludin. Moreover, catalpol concurrently downregulated the mRNA and protein levels of RhoA, and ROCK2, the critical proteins in the RhoA/ROCK2 signaling pathway. This study thus indicated that catalpol, via inhibition of the RhoA/ROCK2 signaling pathway, reverses the disaggregation of cytoskeleton actin in BMECs and prevents down-regulation of junctional proteins, such as claudin-5, occludin, and ZO-1, and decreases endothelin-1 and inflammatory cytokine secretion, eventually alleviating the increase in LPS-induced BBB permeability.http://www.mdpi.com/1420-3049/23/9/2371catalpolLPSBBBtight junctionRhoA/ROCK2 |
| spellingShingle | Shan Feng Li Zou Hongjin Wang Ran He Ke Liu Huifeng Zhu RhoA/ROCK-2 Pathway Inhibition and Tight Junction Protein Upregulation by Catalpol Suppresses Lipopolysaccaride-Induced Disruption of Blood-Brain Barrier Permeability Molecules catalpol LPS BBB tight junction RhoA/ROCK2 |
| title | RhoA/ROCK-2 Pathway Inhibition and Tight Junction Protein Upregulation by Catalpol Suppresses Lipopolysaccaride-Induced Disruption of Blood-Brain Barrier Permeability |
| title_full | RhoA/ROCK-2 Pathway Inhibition and Tight Junction Protein Upregulation by Catalpol Suppresses Lipopolysaccaride-Induced Disruption of Blood-Brain Barrier Permeability |
| title_fullStr | RhoA/ROCK-2 Pathway Inhibition and Tight Junction Protein Upregulation by Catalpol Suppresses Lipopolysaccaride-Induced Disruption of Blood-Brain Barrier Permeability |
| title_full_unstemmed | RhoA/ROCK-2 Pathway Inhibition and Tight Junction Protein Upregulation by Catalpol Suppresses Lipopolysaccaride-Induced Disruption of Blood-Brain Barrier Permeability |
| title_short | RhoA/ROCK-2 Pathway Inhibition and Tight Junction Protein Upregulation by Catalpol Suppresses Lipopolysaccaride-Induced Disruption of Blood-Brain Barrier Permeability |
| title_sort | rhoa rock 2 pathway inhibition and tight junction protein upregulation by catalpol suppresses lipopolysaccaride induced disruption of blood brain barrier permeability |
| topic | catalpol LPS BBB tight junction RhoA/ROCK2 |
| url | http://www.mdpi.com/1420-3049/23/9/2371 |
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