Simvastatin Inhibits Leukocyte Accumulation and Vascular Permeability in the Retinas of Rats with Streptozotocin-Induced Diabetes

Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.
American Journal Of Pathology (Impact Factor: 4.59). 06/2004; 164(5):1697-706. DOI: 10.1016/S0002-9440(10)63728-5
Source: PubMed


Leukocytes play important roles in the pathogenesis of diabetic retinopathy. Recently, 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors have been reported to exert various effects in addition to their lipid-lowering ability. We investigated the effects of simvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, on leukocyte-induced diabetic changes in retinas. Diabetes was induced in Long-Evans rats with streptozotocin, and simvastatin administration was begun immediately after the induction of diabetes. Two weeks of treatment with simvastatin suppressed significantly the number of leukocytes adhering to retinal vessel endothelium and the number of leukocytes accumulated in the retinal tissue by 72.9% and 41.0%, respectively (P < 0.01). The expression of intercellular adhesion molecule-1 (ICAM-1) and the CD18 (the common beta-chain of ICAM-1 ligands) were both suppressed with simvastatin. The amount of vascular endothelial growth factor in the retina was attenuated in the simvastatin-treated group. To evaluate the effects of simvastatin on leukocyte-induced endothelial cell damage, vascular permeability in the retina was measured with fluorescein-labeled dextran. Treatment with simvastatin markedly reduced retinal permeability (P = 0.014). This suggests that simvastatin attenuates leukocyte-endothelial cell interactions and subsequent blood-retinal barrier breakdown via suppression of vascular endothelial growth factor-induced ICAM-1 expression in the diabetic retina. Simvastatin may thus be useful in the prevention of diabetic retinopathy.


Available from: Kazuaki Nishijima
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    • "These techniques, along with others including Evans blue, FITC-albumin extravasation, and isotope dilution have been used to infer changes in the retinal vascular permeability (Miyamoto et al., 1999; Vinores, 1995). It has been demonstrated by several groups that FITC-dextran is a better predictor of BRB leakage as compared to Evans blue in terms of sensitivity and quantification (Atkinson et al., 1991; Ishida et al., 2003; Miyahara et al., 2004; Stitt et al., 2000). Further, selective breakdown of the BRB can be assessed by using FITC-dextrans with different molecular weights (4.4, "
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    ABSTRACT: To determine the efficacy of pazopanib eye drops in the streptozotocin induced diabetic retinopathy rat model. A 0.5% w/v pazopanib suspension was prepared in phosphate buffered saline (PBS, pH 7.4) in the presence of 0.5% w/v sodium carboxymethyl cellulose. Brown Norway rats were divided into three groups (n=4) - (1) healthy, (2) diabetic, and (3) diabetic with treatment. The drug suspension was administered twice daily as eye drops to group 3 for 30 days. Efficacy parameters including the number of adherent leukocytes in the retinal vasculature (leukostasis), blood-retinal FITC-dextran leakage, and vitreous-to-plasma protein ratio were measured. Pazopanib suspension in the form of eye drops significantly reduced leukostasis (32%), FITC-dextran leakage (39%), and the vitreous-to-plasma protein ratio (64%) in diabetic animals compared to untreated diabetic group. Pazopanib eye drops can alleviate retinal complications of diabetic retinopathy.
    Microvascular Research 09/2011; 82(3):346-50. DOI:10.1016/j.mvr.2011.09.001 · 2.13 Impact Factor
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    • "As regards protection of the retina, several statins were previously reported to protect the retina against diabetic retinopathy which is in line with the results of the present work. Simvastatin could retard the progression of retinopathy in diabetic patients with hypercholesrterolemia (Sen, 2002) and exhibited retinal protective effect in rats with experimental diabetes (Al-Shabrawey, 2008; Miyahara, 2004). Lovastatin was reported to protect the blood retinal barrier and ameliorates retinal inflammation in diabetic mice (Li, 2009). "
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    ABSTRACT: The aim of the present work is to investigate the potential retinal neuroprotective effects of atorvastatin in a diabetic hypercholesterolemic animal model in rats and the possible development of hepatotoxicity as a drug adverse effect. Twenty four albino Wistar rats of both sexes were used and divided into four groups; two groups (I and II) served as controls. In group III, diabetes was induced by a single intraperitoneal injection of alloxan 120 mg/kg. Hypercholesterolemia was also induced by addition of cholesterol to the animal diet (10 grams cholesterol/ 1kg diet). In group IV, diabetes and hypercholesterolemia were induced and rats received atorvastatin in a dose of 5 mg/kg daily orally for two months. Serum levels of glucose, cholesterol, triglycerides, total antioxidants, alanine aminotransferase (ALT) and asparate aminotransferse (AST) were measured after 1 and 2 months. Then, animals were sacrificed and subjected to light microscopic examination of the retina and liver. Untreated diabetic hypercholesterolemic animals exhibited significant deterioration of the measured biochemical parameters; elevation of serum levels of glucose, cholesterol, triglycerides, ALT and AST and significant decrease in serum total antioxidants in addition to marked histopathological changes of the retina and liver. Treatment with atorvastatin in group IV improved significantly the diabetes-induced deterioration of serum cholesterol, triglyceride and total antioxidants together with significant improvement of retinal histopathological picture as compared to untreated model of group III suggesting its protective role against diabetic retinopathy. However, there was insignificant effect on the AST serum level and the histopathological picture of the liver in addition to significant deterioration of serum level of ALT when comparing group IV with group III. In conclusion, atorvastatin can partially protect the retina against the development of diabetic retinopathy but care should be taken as regards the hepatotoxic effect of the drug.
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