TY - JOUR T1 - A therapeutic combination of GPCR modulators that protects photoreceptors from degeneration JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.117.245167 SP - jpet.117.245167 AU - Tivadar Orban AU - Henri Leinonen AU - Tamar Getter AU - Zhiqian Dong AU - Wenyu Sun AU - Songqi Gao AU - Alexander Veenstra AU - Hossein Heidari-Torkabadi AU - Timothy S Kern AU - Philip D Kiser AU - Krzysztof Palczewski Y1 - 2017/01/01 UR - http://jpet.aspetjournals.org/content/early/2017/11/21/jpet.117.245167.abstract N2 - Degeneration of retinal photoreceptor cells can arise from environmental and/or genetic causes. Since photoreceptor cells, the retinal pigment epithelium (RPE), neurons and glial cells of the retina are intimately associated; all cell types eventually are affected by retinal degenerative diseases. Such diseases often originate either in rod and/or cone photoreceptor cells or the RPE. Of these, cone cells located in the central retina are especially important for daily human activity. Here we describe the protection of cone cells by a combination therapy consisting of the G protein-coupled receptor modulators metoprolol, tamsulosin, and bromocriptine. These drugs were tested in Abca4-/-Rdh8-/- mice, a preclinical model for retinal degeneration. The specificity of these drugs was determined with an essentially complete panel of human G protein-coupled receptors. Significantly, the combination of metoprolol, tamsulosin, and bromocriptine had no deleterious effects on electroretinographic responses of wild-type mice. Moreover, putative G protein-coupled receptor targets of these drugs were shown to be expressed in human and mouse eyes by RNA sequencing and quantitative PCR. Liquid-chromatography together with mass spectrometry using validated internal standards confirmed that metoprolol, tamsulosin, and bromocriptine individually or together penetrate the eye following either intraperitoneal delivery or oral gavage. Collectively, these findings support human trials with combined therapy comprised of lower doses of metoprolol, tamsulosin, and bromocriptine designed to safely impede retinal degeneration associated with certain genetic diseases (e.g. Stargardt disease). The same low dose combination also could protect the retina against diseases with complex or unknown etiologies such as age-related macular degeneration. ER -