Modulation of ?-adrenoceptor signalling protects photoreceptors after retinal detachment by inhibiting oxidative stress and inflammation.

ABSTRACT: BACKGROUND AND PURPOSE:Currently available treatments do not halt progression of photoreceptor death and subsequent visual impairment related to retinal detachment (RD) which is observed in various retinal disorders. This study investigated the neuroprotective effects of two adrenoceptor ligands, the ?1 -adrenoceptor antagonist doxazosin and the ?2 -adrenoceptor agonist guanabenz, against photoreceptor cell death in RD. EXPERIMENTAL APPROACH:We used a model of experimental RD in Brown-Norway rats induced by subretinal injection of sodium hyaluronate. Oxidative stress biomarkers and cytokine production were quantified with elisa. Protein expression levels and immunofluorescent labelling were determined in rats with RD and controls for mechanistic elucidation. The effects of systemic (i.p.) administration of doxazosin or guanabenz on photoreceptor apoptosis, retinal histology and electroretinography were evaluated in rats with RD and compared to the effects in vehicle controls. KEY RESULTS:Photoreceptors were the major source of RD-induced ROS overproduction in the rat retina through the regulation of NADPH oxidase. Systemic administration of doxazosin or guanabenz decreased the RD-induced production of ROS and proinflammatory cytokines, including IL-1? and the chemokine CCL2, and suppressed retinal gliosis, resulting in attenuation of photoreceptor death and preservation of retinal structures and functions in RD. CONCLUSIONS AND IMPLICATIONS:Our findings point to ?-adrenoceptors as novel therapeutic targets to provide photoreceptor protection and suggest that both doxazosin and guanabenz, two FDA-approved drugs, could be further explored to treat retinal diseases.

SUBMITTER: Li T 

PROVIDER: S-EPMC6393234 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature