EDG Receptors as a Therapeutic Target in Retinal Ischemic Injury

Abstract

Abstract: : Purpose: EDG receptors are a family of G–protein coupled receptors that play an important role in cell growth, development and maintenance, survival and cytoskeletal changes. They exert their effect via intracellular signaling pathways involving various kinases. The purpose of this study was to evaluate the role of lysophosphatidic acid (LPA) –specific EDG receptors (EDG–2 and EDG–4) as therapeutic targets in a model of retinal ischemia. Methods: Transient retinal ischemia was induced in Sprague–Dawley rats by increasing the intraocular pressure above systolic arterial pressure(HIOP) for 45 minutes. Immunohistochemistry for EDG receptor was performed at different times following reperfusion. In a separate set of experiments, intravitreal injections of a novel analog of LPA, LXR 1035, was given 6 hours before and 5 minutes after ischemia (HIOP). These animals were sacrificed at 7 days and retinal tissue harvested to evaluate retinal thickness and cell counts. Retinal function was evaluated by electroretinograms (ERG’s). Results: EDG–2 and EDG–4 receptor staining was maximally evident at 24 hours following ischemia in the ganglion cell layer and the inner nuclear layer as compared to the sham group of animals where no staining was noted. The LXR 1035– treated group of animals showed significant preservation of retinal thickness, cell counts and retinal function as compared to the vehicle–treated group of animals. Conclusions: The neuroprotective effect of EDG receptors in retinal ischemia–reperfusion maybe mediated via activation of phosphatidylinositol 3–kinase, Akt and MAPK and inhibiting cyclic AMP production. Therapies aimed at manipulating these receptors offers potential targets for therapeutic strategies for ischemic retinal disorders.

Keywords: apoptosis/cell death • ischemia • retina