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

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.

Neuroprotective Properties of Dimethyl Fumarate Measured by Optical Coherence Tomography in Non-inflammatory Animal Models

“…Numerous other studies in rodents investigating retinal degeneration after ONC also found a decrease of the RNFL and TRT, as well as a loss of retinal ganglion cells ( 26 – 29 ). After a light-induced retinal damage, authors essentially found degeneration of the ORL and photoreceptors, in line with our results ( 30 , 31 ).…”

Homeostatic plasticity in the retina is associated with maintenance of night vision during retinal degenerative disease

“…Retina whole mounts for cone population analyses were performed as described earlier ( Leinonen et al, 2019 ). In brief, the superior side of each eye was marked with a permanent marker before enucleation.…”

A p97/Valosin-Containing Protein Inhibitor Drug CB-5083 Has a Potent but Reversible Off-Target Effect on Phosphodiesterase-6

“…Histology and OCT were performed as described earlier (Leinonen et al 2019;Leinonen 2020). OCT imaging using a Bioptigen spectral-domain OCT device (Leica Microsystems Inc., Buffalo Grove, IL) was performed after the in vivo ERG recordings while the animals were under the same anesthesia (vehicle-treated VCP mice, n=5; CB-5083-treated VCP mice, n=4; non-treated WT mice, n=3).…”