Abstract

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-α (TNF-α) and tight junction proteins (ZO-1 and claudin-5), and the phosphorylations of nuclear factor-kappa B (NF-κB) 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-α and the phosphorylation levels of NF-κB and c-Jun in the retina after I/R. In addition, cilostazol prevented TNF-α-induced reduction of ZO-1 and claudin-5 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-α-induced NF-κB/AP-1 signaling pathway.

Highlights

  • Ocular ischemic syndrome (OIS) is a condition that is caused by ocular hypoperfusion due to stenosis or occlusion of the common or internal carotid arteries

  • The groups treated with cilostazol (3 and 30 mg/kg) significantly reduced the decreases in cell number in ganglion cell layer (GCL) induced by ischemia (Fig. 1B)

  • The present result, that cilostazol prevented the retinal damage after I/R, is in agreement with previous reports about optic nerve injury and cerebral ischemic injury induced by ligation of the optic sheath and middle cerebral artery occlusion, respectively (Iwama et al 2007; Nonaka et al 2009a)

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Summary

Introduction

Ocular ischemic syndrome (OIS) is a condition that is caused by ocular hypoperfusion due to stenosis or occlusion of the common or internal carotid arteries. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics We reported a new murine OIS model in which both the pterygopalatine artery (PPA) and the external carotid artery (ECA) were ligated (Ogishima et al 2011). This animal model is useful both for the clarification of the pathologic mechanisms underlying OIS and for the evaluation of neuroprotective drugs that might be used to target that syndrome

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