fumarates and Leukostasis

Kinin B(1) receptor (B(1)R) is upregulated in retina of Streptozotocin (STZ)-diabetic rats and contributes to vasodilation of retinal microvessels and breakdown of the blood-retinal barrier. Systemic treatment with B(1)R antagonists reversed the increased retinal plasma extravasation in STZ rats. The present study aims at determining whether ocular application of a water soluble B(1)R antagonist could reverse diabetes-induced retinal inflammation and oxidative stress.. Wistar rats were made diabetic with STZ (65 mg/kg, i.p.) and 7 days later, they received one eye drop application of LF22-0542 (1% in saline) twice a day for a 7 day-period. The impact was determined on retinal vascular permeability (Evans blue exudation), leukostasis (leukocyte infiltration using Fluorescein-isothiocyanate (FITC)-coupled Concanavalin A lectin), retinal mRNA levels (by qRT-PCR) of inflammatory (B(1)R, iNOS, COX-2, ICAM-1, VEGF-A, VEGF receptor type 2, IL-1β and HIF-1α) and anti-inflammatory (B(2)R, eNOS) markers and retinal level of superoxide anion (dihydroethidium staining).. Retinal plasma extravasation, leukostasis and mRNA levels of B(1)R, iNOS, COX-2, VEGF receptor type 2, IL-1β and HIF-1α were significantly increased in diabetic retinae compared to control rats. All these abnormalities were reversed to control values in diabetic rats treated with LF22-0542. B(1)R antagonist also significantly inhibited the increased production of superoxide anion in diabetic retinae.. B(1)R displays a pathological role in the early stage of diabetes by increasing oxidative stress and pro-inflammatory mediators involved in retinal vascular alterations. Hence, topical application of kinin B(1)R antagonist appears a highly promising novel approach for the treatment of diabetic retinopathy.

Topics: Acrylamides; Animals; Anti-Inflammatory Agents; Bradykinin B1 Receptor Antagonists; Cell Membrane Permeability; Cyclooxygenase 2; Diabetes Mellitus, Experimental; Fumarates; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammation; Interleukin-1beta; Leukostasis; Nitric Oxide Synthase Type II; Oxidative Stress; Rats; Rats, Wistar; Receptor, Bradykinin B1; Retina; RNA, Messenger; Streptozocin; Superoxides; Vascular Endothelial Growth Factor Receptor-2