Cilostazol inhibits the redistribution of the actin cytoskeleton and junctional proteins on the blood-brain barrier under hypoxia/reoxygenation.
Cilostazol is a selective inhibitor of cyclic nucleotide phosphodiesterase 3 (PDE3), which induces a vasodilatoric antiplatelet effect. In the present study, we investigated the impact of cilostazol on the blood-brain barrier (BBB), while focusing on the actin cytoskeleton (F-actin), the permeability of endothelial cells, and the junctional proteins under hypoxia/reoxygenation (H/R). Cilostazol was thus found to inhibit the cytoskeletal reorganization under H/R, in which F-actin decrease at the cell periphery. Accordingly, cilostazol was able to attenuate the hyperpermeability of endothelial cells in H/R to the level of the permeability in normoxia. However, the adherens junction (AJ) protein VE-cadherin was not preserved in the presence of cilostazol under H/R. On the other hand, beta-catenin was slightly retained by cilostazol. In contrast to the redistribution of these proteins, immunoblotting demonstrated the total amount of AJ and tight junction (TJ) proteins (occludin, ZO-1 and ZO-2) to not show any significant change under H/R stress in either the presence or absence of cilostazol. Taken together, cilostazol potently displayed a protective effect against acute ischemia by preventing an increase in the endothelial permeability through the preservation of the actin cytoskeleton and the redistribution of junctional proteins.
Torii
Hiroaki
H
Department of Neurosurgery, Yamaguchi University School of Medicine, 1-1-1 Minamikogushi, Ube-City, Yamaguchi 755-8505, Japan.
Kubota
Hisashi
H
Ishihara
Hideyuki
H
Suzuki
Michiyasu
M
D000199:Actins / Q000378:metabolism*; D022005:Adherens Junctions / Q000187:drug effects / Q000378:metabolism; D015703:Antigens, CD / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000378:metabolism*; D015820:Cadherins / Q000378:metabolism; D015687:Cell Hypoxia; D002460:Cell Line; D002463:Cell Membrane Permeability / Q000187:drug effects; D000077407:Cilostazol; D003599:Cytoskeleton / Q000187:drug effects* / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D007365:Intercellular Junctions / Q000187:drug effects* / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D010100:Oxygen / Q000494:pharmacology*; D010750:Phosphoproteins / Q000378:metabolism; D021381:Protein Transport; D013777:Tetrazoles / Q000494:pharmacology*; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism; D062826:Zonula Occludens-1 Protein; D062827:Zonula Occludens-2 Protein; D000099152:Cadherin 5
D000199:Actins; D015703:Antigens, CD; D015820:Cadherins; D000077407:Cilostazol; D008565:Membrane Proteins; D010100:Oxygen; D010750:Phosphoproteins; D013777:Tetrazoles; D062826:Zonula Occludens-1 Protein; D062827:Zonula Occludens-2 Protein; D000099152:Cadherin 5; C569042:TJP1 protein, human; C569046:TJP2 protein, human