Plant-derived triterpene celastrol ameliorates oxygen glucose deprivation-induced disruption of endothelial barrier assembly via inducing tight junction proteins.
BACKGROUND
The integrity and functions of blood-brain barrier (BBB) are regulated by the expression and organization of tight junction proteins.


OBJECTIVE
The present study was designed to explore whether plant-derived triterpenoid celastrol could regulate tight junction integrity in murine brain endothelial bEnd3 cells.


METHODS
We disrupted the tight junctions between endothelial bEnd3 cells by oxygen glucose deprivation (OGD). We investigated the effects of celastrol on the permeability of endothelial monolayers by measuring transepithelial electrical resistance (TEER). To clarify the tight junction composition, we analyzed the expression of tight junction proteins by RT-PCR and Western blotting techniques.


RESULTS
We found that celastrol recovered OGD-induced TEER loss in a concentration-dependent manner. Celastrol induced occludin, claudin-5 and zonula occludens-1 (ZO-1) in endothelial cells. As a result, celastrol effectively maintained tight junction integrity and inhibited macrophage migration through endothelial monolayers against OGD challenge. Further mechanistic studies revealed that celastrol induced the expression of occludin and ZO-1) via activating MAPKs and PI3K/Akt/mTOR pathway. We also observed that celastrol regulated claudin-5 expression through different mechanisms.


CONCLUSIONS
The present study demonstrated that celastrol effectively protected tight junction integrity against OGD-induced damage. Thus, celastrol could be a drug candidate for the treatment of BBB dysfunction in various diseases.
School of Chinese Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong, China.
Dan
D
Luo
School of Chinese Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong, China.
Jia
J
Zhao
School of Chinese Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong, China. Electronic address: jrong@hku.hk.
Jianhui
J
Rong
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D062507:Claudin-5 / Q000235:genetics / Q000378:metabolism; D017097:Electric Impedance; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D062793:Occludin / Q000235:genetics / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism*; D053978:Pentacyclic Triterpenes; D010539:Permeability; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D062725:Tight Junction Proteins / Q000235:genetics / Q000378:metabolism*; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism; D014315:Triterpenes / Q000494:pharmacology*; D062826:Zonula Occludens-1 Protein / Q000235:genetics / Q000378:metabolism
D062507:Claudin-5; D005947:Glucose; D020928:Mitogen-Activated Protein Kinases; D062793:Occludin; D010100:Oxygen; D053978:Pentacyclic Triterpenes; D019869:Phosphatidylinositol 3-Kinases; D062725:Tight Junction Proteins; D014315:Triterpenes; D062826:Zonula Occludens-1 Protein; C491511:Cldn5 protein, mouse; C568986:Ocln protein, mouse; C569043:Tjp1 protein, mouse; C050414:celastrol
Blood-brain barrier; Celastrol; Oxygen glucose deprivation; Signal transduction; Tight junction proteins