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Statin Inhibits Leukocyte-Endothelial Interaction and Prevents Neuronal Death Induced by Ischemia-Reperfusion Injury in the Rat Retina
Megumi Honjo, MD, PhD;
Hidenobu Tanihara, MD, PhD;
Kazuaki Nishijima, MD;
Junichi Kiryu, MD, PhD;
Yoshihito Honda, MD, PhD;
Beatrice Y. J. T. Yue, PhD;
Tatsuya Sawamura, MD, PhD
Arch Ophthalmol. 2002;120:1707-1713.
Background Retinal ishchemia–induced neuronal death is believed to be a direct causal process in the development of many ocular diseases. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, statin, is known to improve endothelial function in proinflammatory conditions.
Objective To investigate the effects of statin on leukocyte accumulation during ischemia-reperfusion injury and on subsequent retinal damage.
Methods Transient retinal ischemia was induced in Long-Evans rats for 60 minutes using temporal ligation of the optic nerve. Leukocyte-endothelial interactions in the postischemic retina were evaluated in vivo with a scanning laser ophthalmoscope. Statin was administered 5 minutes before the induction of retinal ischemia. P-selectin and intercellular adhesion molecule-1 (ICAM-1) gene expression in the postischemic retina were studied with the semiquantitative polymerase chain reaction. Histologic studies were carried out to evaluate retinal damage.
Results The preadministration of statin attenuated the rolling and accumulation of leukocytes, decreased P-selectin and ICAM-1 expression, and reduced the number of apoptotic cells in the retina. Furthermore, histologic evaluation 168 hours after reperfusion showed that statin significantly diminished the resultant retinal tissue damage. The neuroprotective effect of statin was abolished when it was administered along with a nitric oxide synthase inhibitor, nitroglycerine-nitro-L-arginine methyl ester.
Conclusion Statin may exert neuroprotective effects by inhibiting leukocyte-endothelial interaction through the release of nitric oxide from the endothelium.
Clinical Relevance As a result of its efficacy in preventing retinal neuronal death, statin may be developed into a novel therapeutic modality for many ocular ischemic diseases.
From the Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan (Drs Honjo, Nishijima, Kiryu, and Honda); Department of Ophthalmology, Kumamoto University School of Medicine, Kumamoto, Japan (Dr Tanihara); Department of Ophthalmology and Visual Sciences, College of Medicine, University of Illinois at Chicago (Dr Yue); and the Department of Bioscience, National Cardiovascular Center Research Institute, and Department of Molecular Pathophysiology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan (Dr Sawamura).
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