title: 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 (heterotrimeric 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.
authors.affiliation: Yueyang Hospital and Clinical Research Institute of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China. Department of Pharmacology, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA. chenyu6639@hotmail.com kxp65@case.edu.
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Polgenix Inc., Cleveland, OH 44106, USA.
authors.forename: Grazyna
authors.initials: G
authors.lastname: Palczewska
authors.affiliation: Department of Neuroscience, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA.
authors.forename: Ikuo
authors.initials: I
authors.lastname: Masuho
authors.affiliation: Department of Pharmacology, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA.
authors.forename: Songqi
authors.initials: S
authors.lastname: Gao
authors.affiliation: Department of Pharmacology, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Jin
authors.affiliation: Polgenix Inc., Cleveland, OH 44106, USA.
authors.forename: Zhiqian
authors.initials: Z
authors.lastname: Dong
authors.affiliation: Neurobiology-Neurodegeneration and Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Linn
authors.initials: L
authors.lastname: Gieser
authors.affiliation: Neurobiology-Neurodegeneration and Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Brooks
authors.affiliation: Department of Pharmacology, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA. Research Service, Louis Stokes Cleveland VA Medical Center, Cleveland, OH 44106, USA.
authors.forename: Philip D
authors.initials: PD
authors.lastname: Kiser
authors.affiliation: Department of Pharmacology, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA. Research Service, Louis Stokes Cleveland VA Medical Center, Cleveland, OH 44106, USA. Department of Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Kern
authors.affiliation: Department of Neuroscience, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA.
authors.forename: Kirill A
authors.initials: KA
authors.lastname: Martemyanov
authors.affiliation: Neurobiology-Neurodegeneration and Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Anand
authors.initials: A
authors.lastname: Swaroop
authors.affiliation: Department of Pharmacology, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA. Polgenix Inc., Cleveland, OH 44106, USA. chenyu6639@hotmail.com kxp65@case.edu.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Palczewski
mesh_terms: D018663:Adrenergic Agents / Q000494:pharmacology*; D000818:Animals; D015259:Dopamine Agents / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism* / Q000473:pathology; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012162:Retinal Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics
chemical_list: D018663:Adrenergic Agents; D015259:Dopamine Agents; D043562:Receptors, G-Protein-Coupled