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Robin H Schmidt, Preston E Girardot, Jana Terrell Sellers, Micah A Chrenek, Jeffrey H Boatright; Modeling Pharmacological Treatment of Retinitis Pigmentosa with Heterozygous Tvrm4 Rhodopsin Mutant Mice. Invest. Ophthalmol. Vis. Sci. 2017;58(8):3595. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Pharmacological treatments for retinitis pigmentosa (RP), a disease characterized by progressive loss of vision, can be challenging to develop and test. The mostly widely-used mouse models of RP are transgenic strains. The Rho(Tvrm4/+) mouse, a model of Class B phenotype RP, carries a single point mutation in the gene that encodes rhodopsin, causing retinal degeneration after brief exposure to bright light. In contrast to transgenic models, the degeneration process that occurs in the Rho(Tvrm4/+) mouse model is inducible, allowing for more precise coordination of drug administration with particular stages in disease progression. We tested the ability of the neuroprotectant tauroursodeoxycholic acid (TUDCA) to prevent retinal degeneration in the Rho(Tvrm4/+) mouse.
TUDCA (500 mg/kg) was injected i.p. in Rho(Tvrm4/+) mice (N=5 for each group) prior to light exposure. Pupils were dilated by applying a 0.2% atropine solution. After 30 minutes, mice were exposed to 12,000 lux LED white light for 5 minutes. Mice were then returned to maintenance housing and TUDCA administered every 3 days thereafter. Retinal function was assessed by electroretinography (ERG) and visual function assessed by optokinetic tracking (OKT). Eyes were removed at sacrifice for histology and gene transcription analysis by ddPCR. Photoreceptor nuclei were counted in histological sections stained with toluidine blue.
ERG analysis showed that TUDCA treatment completely prevented changes in a- and b-wave amplitude (p<0.0001). TUDCA preserved the number of photoreceptors in light-exposed mice (p=0.0002). Protection against degeneration coincided with decreased mRNA transcripts of genes regulating the complement system. TUDCA treatment had no effect on retinal structure or visual function in mice that were not exposed to bright light.
TUDCA-treated Rho(Tvrm4/+) mice were protected against loss of visual function caused by brief bright light exposure. TUDCA treatment also showed near-complete preservation of retinal morphology and photoreceptor cell numbers. Our data support the use of TUDCA in RP, and potentially in other retinal degenerative diseases. Additionally, the predictable triggering of retinal degeneration in the Rho(Tvrm4/+) mouse means that this genetic model may be useful for testing other candidate drugs.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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