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In DME, corticosteroids stabilize the existing retinal vasculature and are antiangiogenic, directly suppressing the production of paracrine angiogenic factors, including VEGF, and reducing the formation of new blood vessels.12,39 Through repression of key pro-inflammatory transcription factors, such as nuclear factor-kappa B (NF��B) and activator protein 1, the pro-inflammatory feedback loop established in macular edema is disrupted.13,23 Corticosteroids inhibit phospholipase A2,12 which is upregulated in the retinal microvasculature of the streptozotocin-induced diabetic rat40,41 and is implicated in retinal VEGF, ICAM-1, and TNF-�� expression and retinal edema formation.41,42 Corticosteroids also induce expression of several anti-inflammatory proteins, including IL-10, adenosine, and I��B��, the natural inhibitor of NF��B,35 actively dampening the reaction. Intravitreal dexamethasone has been shown to reduce retinal leukostasis and vascular endothelial ICAM-1 expression in the diabetic rat model.43 At the BRB, corticosteroids act to maintain tight junction integrity by promoting tight junction protein expression and translocation to the endothelial/epithelial cell border,28 and by protecting against oxidative stress-induced disruption of tight junction proteins in retinal pigment epithelial cells.44 In addition to reducing retinal vascular permeability, corticosteroids also promote retinal fluid clearance through their effects on transcellular aquaporin-4 (AQP4) and potassium channels, the two main channels controlling retinal fluid movement on retinal M��ller cells.45,46 The commonly used ocular corticosteroids, dexamethasone, triamcinolone acetonide, and fluocinolone acetonide, differ in their glucocorticoid receptor-binding affinity (dexamethasone > triamcinolone acetonide > fluocinolone acetonide) and lipophilicity (triamcinolone acetonide > fluocinolone acetonide > dexamethasone),34 which could potentially translate into clinically important differences in ocular activity. Barriers to intraocular delivery of corticosteroids The principal challenge in pharmacotherapy of retinal disease is how to allobarbital achieve effective and sustained intraretinal drug concentrations while minimizing unwanted drug effects on other ocular structures. Ocular penetration of systemically administered drugs (particularly large and/or hydrophilic molecules) is restricted by the BRB, which comprises the tight junctions of the retinal vascular endothelium (inner BRB) and the retinal pigment epithelium (outer BRB). For those drugs that do cross the BRB (small lipophilic molecules), the diluting effect of blood volume requires the use of large systemic doses, with the attendant risk of systemic adverse effects, while the rapid flow rate in the choroidal and retinal circulation limits drug exposure time. The topically applied drug has to diffuse through multiple ocular tissues to reach the posterior segment of the eye.