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

Henri Leinonen,Krzysztof Palczewski,Anthony Gardella,Elliot H Choi,Vladimir J Kefalov

doi:10.1167/iovs.19-26560

Abstract

PurposeThe 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 Gi, Gs, and Gq protein-coupled receptors.MethodsAcute 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 (β1-receptor antagonist), bromocriptine (dopamine family-2 receptor agonist) and tamsulosin (α1-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.ResultsThe Gnat1−/− mice showed slightly increased susceptibility to rod light damage, whereas the Gnat2−/− mice were very resistant. The Arr1−/− and Grk1−/− 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 Gnat1−/− mice. The therapeutic drug doses increased in parallel with light-damage severity.ConclusionsOur 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 Gi signaling and attenuate Gs and Gq signaling present a promising disease-modifying therapy for photoreceptor degenerative diseases.

Highlights

Gnat[1] mutant Gnat[2] mutant Grk[1] mutant Arr[1] mutant BALB/cJ wild-type n.a., not applicable.129S1/SvlmJ C57BL/6J 129S1/SvlmJ C57BL/6J n.a
Two recent clinical reports have implicated the novel type of homozygous GNAT1 mutations into a progressive retinal dystrophy.[27,28]
The first is BLE-induced apoptosis that is independent of transducin

Summary

Introduction

Gnat[1] mutant Gnat[2] mutant Grk[1] mutant Arr[1] mutant BALB/cJ wild-type n.a., not applicable.129S1/SvlmJ C57BL/6J 129S1/SvlmJ C57BL/6J n.a. Once visual arrestin binds to the phosphorylated rhodopsin, the visual pigment is fully inactivated.[10] Proper functioning of the phototransduction cascade, including its efficient shutoff, is a prerequisite for normal vision and a healthy retina. We investigated the extent to which genetic knock-outs of rod and cone transducin (Gnat[1] and Gnat[2], respectively), rhodopsin kinase 1 (Grk1), and visual arrestin 1 (Arr[1], SAG) predispose mice to the damaging effects of light. Light damage in Arr[1] and Grk[1] knock-out mice, both associated with Oguchi disease,[14] was extremely robust, but could be fully prevented with increasing doses of METþBRMþTAM

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