A combination of G protein-coupled receptor modulators protects photoreceptors from degeneration

Tivadar Orban, Henri Leinonen, Tamar Getter, Zhiqian Dong, Wenyu Sun, Songqi Gao, Alexander Veenstra, Hossein Heidari-Torkabadi, Timothy S. Kern, Philip D. Kiser, Krzysztof Palczewski

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

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 receptormodulators 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 wildtype 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 polymerase chain reaction. Liquid chromatography together with mass spectrometry using validated internal standards confirmed that metoprolol, tamsulosin, and bromocriptine individually or together penetrate the eye after either intraperitoneal delivery or oral gavage. Collectively, these findings support human trials with combined therapy composed 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.

Original languageEnglish
Pages (from-to)207-220
Number of pages14
JournalJournal of Pharmacology and Experimental Therapeutics
Volume364
Issue number2
DOIs
StatePublished - Feb 2018
Externally publishedYes

Bibliographical note

Publisher Copyright:
Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

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