A Mixture of U.S. Food and Drug Administration–Approved Monoaminergic Drugs Protects the Retina From Light Damage in Diverse Models of Night Blindness

摘要

Purpose : The purpose of this study was to test the extent of light damage in different models of night blindness and apply these paradigms in testing the therapeutic efficacy of combination therapy by drugs acting on the Gsubi/sub, Gsubs/sub, and Gsubq/sub protein-coupled receptors. Methods : Acute bright light exposure was used to test susceptibility to light damage in mice lacking the following crucial phototransduction proteins: rod transducin (GNAT1), cone transducin (GNAT2), visual arrestin 1 (ARR1), and rhodopsin kinase 1 (GRK1). Mice were intraperitoneally injected with either vehicle or drug combination consisting of metoprolol (βsub1/sub-receptor antagonist), bromocriptine (dopamine family-2 receptor agonist) and tamsulosin (αsub1/sub-receptor antagonist) before bright light exposure. Light damage was primarily assessed with optical coherence tomography and inspection of cone population in retinal whole mounts. Retinal inflammation was assessed in a subset of experiments using autofluorescence imaging by scanning laser ophthalmoscopy and by postmortem inspection of microglia and astrocyte activity. Results : The Gnat1sup?/?/sup mice showed slightly increased susceptibility to rod light damage, whereas the Gnat2sup?/?/sup mice were very resistant. The Arr1sup?/?/sup and Grk1sup?/?/sup mice were sensitive for both rod and cone light damage and showed robust retinal inflammation 7 days after bright light exposure. Pretreatment with metoprolol + bromocriptine + tamsulosin rescued the retina in all genetic backgrounds, starting at doses of 0.2 mg/kg metoprolol, 0.02 mg/kg bromocriptine, and 0.01 mg/kg tamsulosin in the Gnat1sup?/?/sup mice. The therapeutic drug doses increased in parallel with light-damage severity. Conclusions : Our results suggest that congenital stationary night blindness and Oguchi disease patients can be at an elevated risk of the toxic effects of bright light. Furthermore, systems pharmacology drug regimens that stimulate Gsubi/sub signaling and attenuate Gsubs/sub and Gsubq/sub signaling present a promising disease-modifying therapy for photoreceptor degenerative diseases.