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Xu Wang, Lian Zhao, Wenxin Ma, Yikui Zhang, Shaimar Gonzalez, Jianguo Fan, Friedrich Kretschmer, Tudor C Badea, Haohua Qian, Wai T Wong; Tamoxifen provides structural and functional rescue in murine models of photoreceptor degeneration. Invest. Ophthalmol. Vis. Sci. 2017;58(8):5901.
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© ARVO (1962-2015); The Authors (2016-present)
Photoreceptor (PR) degeneration is a cause of irreversible vision loss in incurable blinding retinal diseases including retinitis pigmentosa (RP) and atrophic age-related macular degeneration. Recent studies have implicated non-cell autonomous contributions from microglia to the rate of PR degeneration. We investigate tamoxifen, a selective estrogen receptor modulator (SERM), as an agent to ameliorate PR degeneration via the inhibition of microglial activation.
We evaluated the effects of oral tamoxifen administration (80mg/kg daily) in: (1) a light-induced PR injury model, and (2) the rd10 (Pde6brd10) genetic model for RP. Evaluations performed include in vivo structural imaging (OCT and autofluorescence) and functional testing (ERG and optokinetic response (OKR) measurement), and immunohistological analyses. Cytokine analyses were performed using a Milliplex assay kit. In vitro studies examining microglia-PR interactions were performed.
We found that tamoxifen, a drug previously linked with retinal toxicity, paradoxically provided potent neuroprotective effects in the context of retinal injury. In a light-induced degeneration model, tamoxifen prevented onset of photoreceptor apoptosis and atrophy, and maintained near-normal levels of electroretinographic responses. Rescue effects were correlated with decreased microglial activation and inflammatory cytokine production in the retina in vivo, and a reduction of microglia-mediated toxicity to photoreceptors in vitro, indicating a microglia-mediated mechanism of rescue. Tamoxifen also attenuated degeneration in a genetic (Pde6brd10) model of retinitis pigmentosa, significantly improving retinal structure, electrophysiological responses, and visual behavior.
Tamoxifen exerts prominent neuroprotective effects in two separate mouse models of PR degeneration. Further studies into tamoxifen as a drug suitable for being repurposed to treat PR degeneration in retinal disease are warranted.
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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