Dexamethasone Inhibits Leukocyte Accumulation and Vascular Permeability in Retina of Streptozotocin-Induced Diabetic Rats via Reducing Vascular Endothelial Growth Factor and Intercellular Adhesion Molecule-1 Expression

Abstract

Retinopathy, a major complication of diabetes, often leads to diabetic macular edema which causes adult blindness in many countries. The acetazolamide and topical application of nonsteroidal antiinflammatory drugs (NSAIDs) are helpful in treating macular edema, but their efficacy as therapeutic agent remains to be proved. Glucocorticoids were used to treat the edema caused by brain tumors.1,2) Intravitreal injection of steroids may be used in treating macular edema when oral administration of acetazolamide and topical application of NSAIDs or steroids are not effective.3) Some studies have reported the efficacy and complications of intravitreal triamcinolone acetonide injection and shown the positive results of intravitreal corticosteroid injection. 4,5) However, the exact mechanism of such treatments was not demonstrated and a large-scale, randomized clinical trial was needed to prove their effects.Several lines of evidence suggest that the pathogenesis of diabetic retinopathy is mediated by inflammatory processes, including leukocyte adhesion and the cytokine network. [6][7][8] Retinal vasculature in diabetes is accompanied by inflammatory cell adhesion, which triggers vascular hyperpermeability and pathologic retinal neovascularization. Vascular endothelial growth factor (VEGF) was thought to mediate leukocytes bind to the vasculature, inducing retinal vascular permeability and leukostasis partially through intercellular adhesion molecule-1 (ICAM-1). So, VEGF and ICAM-1 may be two critical factors for diabetes-induced leukostasis and bloodretinal barrier breakdown.The streptozotocin-induced diabetic rat shows many of the early changes in retinal structure and function that are associated with human diabetic retinopathy.9,10) Therefore, in the present experiment, we investigated the effect of dexamethasone on VEGF and ICAM-1 in streptozotocin-diabetic rats. Accumulated leukocytes were counted in vivo by acridine orange leukocyte fluorography, the retinal vascular permeability was measured by the Evans blue assay. The mRNA and protein level of VEGF and ICAM-1 were analyzed with realtime quantitative polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA) respectively. We found that intravitreal dexemethasone injection inhibited VEGF and ICAM-1 expression and reduced leukocyte accumulation, vascular permeability in streptozotocin-induced diabetic rats, which may be the underlying mechanisms of its effect. MATERIALS AND METHODS MaterialsThe experiments were carried out in compliance with the guidelines for animal care and use of China and the experimental protocols were approved by the animal ethics committee of Beijing Capital Medical University. Male pigmented Brown-Norway rats (180 g, nϭ72) were purchased from Vitalriver Laboratory Animals Co., Ltd. (Beijing, China). After an overnight fast, some rats received intraperitoneal streptozotocin injection (60 mg/kg; Sigma Chemical, St. Louis, MO, U.S.A.) in 10 mmol/l citrate buffer (pH 4.5) for diabetes induction. Control nondiabetic animals r...

The PKCβ/HuR/VEGF pathway in diabetic retinopathy

“…Studies of retinal VEGF mRNA expression in STZ-induced diabetic rats have produced conflicting results, with VEGF mRNA concentrations reported to be increased [34,53,54], decreased [55,56] or unchanged [57] in diabetic rats compared with levels in control rats. The present findings show that, following diabetes, there is a higher phosphorylation of the HuR protein by PKCβ resulting in the activation of HuR itself that then targets VEGF mRNA, finally leading to an increased amount of the correspondent VEGF protein (Fig.…”

Signal Transduction Pathways in use of Dexamethasone Implant in the Eye

“…In another animal study, ICAM-1 and VEGF mRNA expressions were up-regulated in the diabetic group, and significantly suppressed 48 hours following the dexamethasone administration [65]. ICAM-1 and VEGF protein levels were 76.74pg/mg in the untreated DM group, which was higher than the control group.…”

“…ICAM-1 and VEGF protein levels were 76.74pg/mg in the untreated DM group, which was higher than the control group. When the ICAM-1 protein level was compared with the diabetic group, it was seen that this was significantly lowered by dexamethasone [65]. In another experimental study, dexamethasone affected the vascular permeability caused by brain tumors in relation with the GR mechanism by decreasing the response to permeability factors of tumoral origin, and by reducing the vascular permeability factor release from tumoral cells [96].…”

“…In an animal study on diabetic retinopathy, it was seen that the proportion of leukocytes reduced by 48% within 48 hours following the dexamethasone administration [65]. It is understood from these data that glucocorticoids or dexamethasone provides the anti-inflammatory effects via several pathways.…”

“…In the intravitreal dexamethasone injection group, however, the leakage was reduced by 47.5%, as compared to the diabetic group. The increase in the levels of cytokine receptor (IL-2Rα, IL-4Rα, IL-6Rα, IFN-ɣR, GM-CSFRα, CSF-1R, TNF-R) induced by glucocorticoids was accompanied by the increase in receptor mRNA [65,66]. Molecular mechanismsby which glucocorticoids inhibit cytokines are reported to be at the level of transcription, translation, mRNA stability and secretion [66].…”