The selective estrogen receptor modulator raloxifene mitigates the effect of all-trans-retinal toxicity in photoreceptor degeneration

  1. Krzysztof Palczewski?,§3
  1. From the ?Gavin Herbert Eye Institute, Department of Ophthalmology, University of California, Irvine, California 92697,
  2. the §Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio 44106,
  3. the ?Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205,
  4. the Wilmer Eye Institute, Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287,
  5. **Polgenix Inc., Irvine, California 92617,
  6. the ??Department of Ophthalmology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, and
  7. the §§McGowan Institute of Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15213
  1. ?1 To whom correspondence may be addressed: Gavin Herbert Eye Institute, Dept. of Ophthalmology, University of California, Irvine, CA 92657. Tel.: 949-824-5154; E-mail: tgetter{at}uci.edu.
  2. ?3 Leopold Chair of Ophthalmology. To whom correspondence may be addressed: Gavin Herbert Eye Institute, Dept. of Ophthalmology, University of California, Irvine, CA 92657. Tel.: 949-824-6527; E-mail: kpalczew{at}uci.edu.
  1. Edited by Henrik G. Dohlman

Abstract

The retinoid cycle is a metabolic process in the vertebrate retina that continuously regenerates 11-cis-retinal (11-cisRAL) from the all-trans-retinal (atRAL) isomer. atRAL accumulation can cause photoreceptor degeneration and irreversible visual dysfunction associated with incurable blinding retinal diseases, such as Stargardt disease, retinitis pigmentosa (RP), and atrophic age-related macular degeneration (AMD). The underlying cellular mechanisms leading to retinal degeneration remain uncertain, although previous studies have shown that atRAL promotes calcium influx associated with cell apoptosis. To identify compounds that mitigate the effects of atRAL toxicity, here we developed an unbiased and robust image-based assay that can detect changes in intracellular calcium levels in U2OS cells. Using our assay in a high-throughput screen of 2,400 compounds, we noted that selective estrogen receptor modulators (SERMs) potently stabilize intracellular calcium and thereby counteract atRAL-induced toxicity. In a light-induced retinal degeneration mouse model (Abca4?/?Rdh8?/?), raloxifene (a benzothiophene-type scaffold SERM) prevented the onset of photoreceptor apoptosis and thus protected the retina from degeneration. The minor structural differences between raloxifene and one of its derivatives (Y 134) had a major impact on calcium homeostasis after atRAL exposure in vitro, and we verified this differential impact in vivo. In summary, the SERM raloxifene has structural and functional neuroprotective effects in the retina. We propose that the highly sensitive image-based assay developed here could be applied for the discovery of additional drug candidates preventing photoreceptor degeneration.

Footnotes

  • ?2 Robert Bond Welch Professor.

  • This research was supported in part by NEI, National Institutes of Health, Grants R24EY024864 and R24EY027283 (to K. P.), EY024992 (to Y. C.), T32GM007250 and F30EY029136-01A1 (to S. S.), and R01EY027691 (to J. T. H.); an unrestricted grant from Research to Prevent Blindness to the Department of Ophthalmology at the University of California (Irvine, CA); the Canadian Institute for Advanced Research (CIFAR); and the Alcon Research Institute (ARI). K. P. is Chief Scientific Officer at Polgenix, Inc. Z. D. and X. M. are employees of Polgenix, Inc. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

  • This article contains Table S1 and Figs. S1–S6.

  • Received April 1, 2019.
  • Revision received May 8, 2019.

Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc.

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This Article

  1. The Journal of Biological Chemistry 294, 9461-9475.
  1. Supporting Information
  2. All Versions of this Article:
    1. RA119.008697v1
    2. 294/24/9461 (most recent)

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