Article

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: 4.6). 06/2004; 164(5):1697-706. DOI: 10.1016/S0002-9440(10)63728-5
Source: PubMed

ABSTRACT 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.

0 Followers
 · 
78 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: ABSTRACT Insulin resistance, a key feature of obesity, metabolic syndrome, and type 2 diabetes mellitus (T2DM), results in a variety of metabolic and vascular abnormalities. Metabolic disturbances associated with diabetes could contribute to disrupting the structural and (or) functional integrity of the retina. The effects of atorvastatin on retinal cells in hyperlipidemic T2DM rats have not yet been investigated. We used Goto–Kakizaki (GK) rats fed with an atherogenic diet (AD) for 4 months to investigate whether atorvastatin (administered for 1 month) would slow-down or reverse the progression of lesions in the diabetic retina. Fluorogenic substrates were used to measure the proteasome activities in retinal cells. The production of reactive oxygen species was determined by immunofluorescence in frozen retina sections, using dihydroethydium. Nitrotyrosine levels were assessed using immunohistochemistry. Protein levels of ubiquitin conjugates, free ubiquitin, and ubiquitin activating enzyme E1 were determined with Western blotting. Atorvastatin significantly reduced the levels of oxidative stress that were induced by the AD and restored the proteasome activities in the diabetic GK rats. Atorvastatin therapy significantly improved local oxidative stress levels in GK rats fed with AD. Atorvastatin can, at least in part, restore the ubiquitin proteasome system, and may represent a pharmacological approach to prevent some of the complications associated with diabetic retinopathy.
    Canadian Journal of Physiology and Pharmacology 10/2014; 92(12):1037-1043. DOI:10.1139/cjpp-2014-0212 · 1.55 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The objective of this study was to analyze the risk factors associated with the hemoglobin and hematocrit drops in the early postoperative period for intertrochanteric fracture patients with intramedullary nailing treatment. From January 2003 to December 2013, 634 intertrochanteric fracture patients with complete information were recruited into the study. Their age, gender, operating time, medical diseases, blood routine examination at admission and postoperative first day, and the days between the trauma and operation were recorded. Results: The hemoglobin (HGB) change of patients (< 75 years) was significantly greater than that of patients (> 75 years) (P = 0.039). Meanwhile, the change of hematocrit (HCT) level of patients (< 75 years) was greater than that of patients (> 75 years), but the difference was not significant (P = 0.062). The gender had no significant influence on HCT and HGB. The HGB and HCT change of patients with diabetes (Delta HCT, 8.47 +/- A 3.36 %; Delta HGB, 29.19 +/- A 13.10 g/l) were statistically greater than that of patients without diabetes (Delta HCT, 5.52 +/- A 3.84 %; Delta HGB, 19.81 +/- A 14.68 g/l) (P = 0.006, P = 0.022). The hypertension and coronary heart disease had no significant influence on the change of HCT and HGB levels. The operation time had a significant influence on the change of HCT and HGB. The Delta HCT and Delta HGB in the group for which the time was more than 48 h between the trauma and operation were greater than that in the group with less than 48 h between the trauma and operation but not significantly different (Delta HCT, P = 0.672; Delta HGB, P = 0.66). The factors of age, medical disease such as diabetes, operation time, and time between the trauma and operation may be associated with the change of perioperative hemoglobin and hematocrit levels for intertrochanteric fracture patients after intramedullary nailing treatment in the early postoperative period.
    Journal of Orthopaedic Science 11/2014; 20(1). DOI:10.1007/s00776-014-0667-3 · 1.01 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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.

Full-text (2 Sources)

Download
30 Downloads
Available from
Jun 4, 2014