Cilostazol prevents retinal ischemic damage partly via inhibition of tumor necrosis factor-alpha-induced nuclear factor-kappa B/activator protein-1 signaling pathway

被引:10
|
作者
Ishizuka, Fumiya [1 ]
Shimazawa, Masamitsu [1 ]
Egashira, Yusuke [1 ,2 ]
Ogishima, Hiromi [1 ]
Nakamura, Shinsuke [1 ]
Tsuruma, Kazuhiro [1 ]
Hara, Hideaki [1 ]
机构
[1] Gifu Pharmaceut Univ, Dept Biofunct Evaluat, Mol Pharmacol, 1-25-4 Daigaku Nishi, Gifu 5011196, Japan
[2] Gifu Univ, Grad Sch Med, Dept Neurosurg, Gifu, Japan
来源
PHARMACOLOGY RESEARCH & PERSPECTIVES | 2013年 / 1卷 / 01期
关键词
Activator protein-1; cilostazol; inflammation; nuclear factor-kappa B; ocular ischemic syndrome; phosphodiesterase III inhibitor; retinal microvascular endothelial cells; tight junction proteins; tumor necrosis factor-alpha;
D O I
10.1002/prp2.6
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Cilostazol is a specific inhibitor of phosphodiesterase III and is widely used to treat ischemic symptoms of peripheral vascular disease. We evaluated the protective effects of cilostazol in a murine model of ocular ischemic syndrome in which retinal ischemia was induced by 5-h unilateral ligation of both the pterygopalatine artery (PPA) and the external carotid artery (ECA) in anesthetized mice. The effects of cilostazol (30 mg/kg, p. o.) on ischemia/reperfusion (I/R)-induced retinal damage were examined by histological, retinal vascular permeability, and electrophysiological analyses. Using immunoblotting, the protective mechanism for cilostazol was evaluated by examining antiinflammatory effects of cilostazol on the expression of tumor necrosis factors-alpha (TNF-alpha) and tight junction proteins (ZO-1 and claudin-5), and the phosphorylations of nuclear factor-kappa B (NFjB) and c-Jun. The histological analysis revealed that I/R decreased the cell number in the ganglion cell layer (GCL) and the thicknesses of the inner plexiform layer (IPL) and inner nuclear layer (INL), and that cilostazol attenuated these decreases. Additionally, cilostazol prevented the hyperpermeability of blood vessels. Electroretinogram (ERG) measurements revealed that cilostazol prevented the I/R-induced reductions in a-, b-, and oscillatory potential (OP) wave amplitudes seen at 5 days after I/R. Cilostazol inhibited the increased expression of TNF-a and the phosphorylation levels of NF-jB and c-Jun in the retina after I/R. In addition, cilostazol prevented TNF-alpha-induced reduction of ZO-1 and claudin5 expression in human retinal microvascular endothelial cells (HRMECs). These findings indicate that cilostazol may prevent I/R-induced retinal damage partly through inhibition of TNF-a-induced NF-jB/AP-1 signaling pathway.
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页数:12
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