Synergistically acting agonists and antagonists of G protein–coupled receptors prevent photoreceptor cell degeneration

Abstract

Photoreceptor cell degeneration leads to visual impairment and blindness in several types of retinal disease. However, the discovery of safe and effective therapeutic strategies conferring photoreceptor cell protection remains challenging. Targeting distinct cellular pathways with low doses of different drugs that produce a functionally synergistic effect could provide a strategy for preventing or treating retinal dystrophies. We took a systems pharmacology approach to identify potential combination therapies using a mouse model of light-induced retinal degeneration. We showed that a combination of U.S. Food and Drug Administration–approved drugs that act on different G protein (guanine nucleotide–binding protein)–coupled receptors (GPCRs) exhibited synergistic activity that protected retinas from light-induced degeneration even when each drug was administered at a low dose. In functional assays, the combined effects of these drugs were stimulation of Gi/o signaling by activating the dopamine receptors D2R and D4R, as well as inhibition of Gs and Gq signaling by antagonizing D1R and the α1A-adrenergic receptor ADRA1A, respectively. Moreover, transcriptome analyses demonstrated that such combined GPCR-targeted treatments preserved patterns of retinal gene expression that were more similar to those of the normal retina than did higher-dose monotherapy. Our study thus supports a systems pharmacology approach to identify treatments for retinopathies, an approach that could extend to other complex disorders.

Transcriptome profiling of NIH3T3 cell lines expressing opsin and the P23H opsin mutant identifies candidate drugs for the treatment of retinitis pigmentosa

“…This strategy can then be tailored to identify novel and effective compounds or combinations of compounds applicable to the treatment of complex diseases as recently reported in animal models [74] and eventually in humans. …”

Modulation of α‐adrenoceptor signalling protects photoreceptors after retinal detachment by inhibiting oxidative stress and inflammation

“…Moreover, the α 1 ‐adrenoceptors were most abundant in rabbit photoreceptors, while an enrichment of binding sites to α 1 ‐adrenoceptorss was observed in rat outer plexiform layers (Zarbin et al ., ; Wikberg‐Matsson et al ., ). Pharmacological interventions targeting α 1 ‐adrenoceptorss by administration of similar antagonists, such as prazosin and tamsulosin, also protected against photoreceptor loss from light damage (Chen et al ., ). However, further studies are needed to more accurately describe the locations of α 1 ‐adrenoceptors in the retina and determine which subtypes account for the neuroprotective effects these receptors provide against photoreceptor apoptosis.…”

“…In order to minimize dose‐related toxicities and to amplify therapeutic effects, combination therapies with two or more agents could provide rational and effective treatment by activating various signalling cascades or interactional networks that share common effectors or downstream targets. Combination therapies that target different GPCR signalling pathways, such as simultaneous inhibition of G q ‐coupled GPCRs and activation of G i ‐coupled GPCRs, were recently evaluated in animal models of light‐induced retinopathy (Chen et al ., ) or diabetic retinopathy (Du et al ., ). Effective protection against photoreceptor degeneration after light exposure was achieved with combined treatments of two or more GPCR‐targeting drugs at lower doses (e.g.…”

Protective Effect of a Locked Retinal Chromophore Analog against Light-Induced Retinal Degeneration

“…Excessive concentrations of all-trans-retinal that induce oxidative stress through the activation of the phospholipase C (PLC) → inositol-3-phosphate (IP3) → Ca 2+ pathway and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase resulting in photoreceptor death can be prevented with antioxidants , Chen Y et al, 2016, Chen Y et al, 2013.…”