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 retina in vivo and a reduction of microglia-mediated toxicity to photoreceptors in 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 STATEMENT Photoreceptor 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: Xu Wang, Lian Zhao, Yikui Zhang, Wenxin Ma, Shaimar R Gonzalez, Jianguo Fan, Friedrich Kretschmer, Tudor C Badea, Hao-Hua Qian, Wai T Wong
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 37 Issue 12 Pg. 3294-3310 (03 22 2017) ISSN: 1529-2401 [Electronic] United States
• PMID: 28235894 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)
• Copyright: Copyright © 2017 the authors 0270-6474/17/373294-17$15.00/0.

Chemical References

• Neuroprotective Agents
• Tamoxifen

Topics

• Animals
• Apoptosis (drug effects)
• Dose-Response Relationship, Drug
• Female
• Male
• Mice
• Mice, Inbred C57BL
• Nerve Regeneration (physiology, radiation effects)
• Neuroprotective Agents (administration & dosage)
• Photoreceptor Cells, Vertebrate (drug effects, pathology, physiology)
• Recovery of Function (drug effects)
• Retinal Degeneration (drug therapy, pathology, physiopathology)
• Tamoxifen (administration & dosage)
• Treatment Outcome