title: Tamoxifen Provides Structural and Functional Rescue in Murine Models of Photoreceptor Degeneration.
abstract: Photoreceptor degeneration is a cause of irreversible vision loss in incurable blinding retinal diseases including retinitis pigmentosa (RP) and atrophic age-related macular degeneration. We found in two separate mouse models of photoreceptor degeneration that tamoxifen, a selective estrogen receptor modulator and a drug previously linked with retinal toxicity, paradoxically provided potent neuroprotective effects. 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 retinain vivoand a reduction of microglia-mediated toxicity to photoreceptorsin vitro, indicating a microglia-mediated mechanism of rescue. Tamoxifen also rescued degeneration in a genetic (Pde6brd10) model of RP, significantly improving retinal structure, electrophysiological responses, and visual behavior. These prominent neuroprotective effects warrant the consideration of tamoxifen as a drug suitable for being repurposed to treat photoreceptor degenerative disease.SIGNIFICANCE STATEMENTPhotoreceptor degeneration is a cause of irreversible blindness in a number of retinal diseases such as retinitis pigmentosa (RP) and atrophic age-related macular degeneration. Tamoxifen, a selective estrogen receptor modulator approved for the treatment of breast cancer and previously linked to a low incidence of retinal toxicity, was unexpectedly found to exert marked protective effects against photoreceptor degeneration. Structural and functional protective effects were found for an acute model of light-induced photoreceptor injury and for a genetic model for RP. The mechanism of protection involved the modulation of microglial activation and the production of inflammatory cytokines, highlighting the role of inflammatory mechanisms in photoreceptor degeneration. Tamoxifen may be suitable for clinical study as a potential treatment for diseases involving photoreceptor degeneration.
authors.affiliation: Unit on Neuron-Glia Interactions in Retinal Disease.
authors.forename: Xu
authors.initials: X
authors.lastname: Wang
authors.affiliation: Unit on Neuron-Glia Interactions in Retinal Disease.
authors.forename: Lian
authors.identifier: 0000-0002-0120-1969
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Unit on Neuron-Glia Interactions in Retinal Disease.
authors.forename: Yikui
authors.identifier: 0000-0001-8607-8324
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Unit on Neuron-Glia Interactions in Retinal Disease.
authors.forename: Wenxin
authors.initials: W
authors.lastname: Ma
authors.affiliation: Unit on Neuron-Glia Interactions in Retinal Disease.
authors.forename: Shaimar R
authors.initials: SR
authors.lastname: Gonzalez
authors.affiliation: Section on Molecular Structure and Functional Genomics.
authors.forename: Jianguo
authors.identifier: 0000-0003-1051-3283
authors.initials: J
authors.lastname: Fan
authors.affiliation: Retinal Circuit Development and Genetics Unit, and.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Kretschmer
authors.affiliation: Retinal Circuit Development and Genetics Unit, and.
authors.forename: Tudor C
authors.initials: TC
authors.lastname: Badea
authors.affiliation: Visual Function Core, National Eye Institute, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Hao-Hua
authors.identifier: 0000-0002-1114-4697
authors.initials: HH
authors.lastname: Qian
authors.affiliation: Unit on Neuron-Glia Interactions in Retinal Disease, wongw@nei.nih.gov.
authors.forename: Wai T
authors.identifier: 0000-0003-0681-4016
authors.initials: WT
authors.lastname: Wong
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009416:Nerve Regeneration / Q000502:physiology* / Q000528:radiation effects; D018696:Neuroprotective Agents / Q000008:administration & dosage; D020419:Photoreceptor Cells, Vertebrate / Q000187:drug effects* / Q000473:pathology* / Q000502:physiology; D020127:Recovery of Function / Q000187:drug effects; D012162:Retinal Degeneration / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology*; D013629:Tamoxifen / Q000008:administration & dosage*; D016896:Treatment Outcome
chemical_list: D018696:Neuroprotective Agents; D013629:Tamoxifen
keywords: degeneration; microglia; neuroprotection; photoreceptor; retinitis pigmentosa; tamoxifen