Identification of fluoxetine as a direct NLRP3 inhibitor to treat atrophic macular degeneration

Meenakshi Ambati, Ivana Apicella, Shao Bin Wang, Siddharth Narendran, Hannah Leung, Felipe Pereira, Yosuke Nagasaka, Peirong Huang, Akhil Varshney, Kirstie L. Baker, Kenneth M. Marion, Mehrdad Shadmehr, Cliff I. Stains, Brian C. Werner, Srinivas R. Sadda, Ethan W. Taylor, S. Scott Sutton, Joseph Magagnoli, Bradley D. Gelfand

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

Abstract

The atrophic form of age-related macular degeneration (dry AMD) affects nearly 200 million people worldwide. There is no Food and Drug Administration (FDA)-approved therapy for this disease, which is the leading cause of irreversible blindness among people over 50 y of age. Vision loss in dry AMD results from degeneration of the retinal pigmented epithelium (RPE). RPE cell death is driven in part by accumulation of Alu RNAs, which are noncoding transcripts of a human retrotransposon. Alu RNA induces RPE degeneration by activating the NLRP3-ASC inflammasome. We report that fluoxetine, an FDA-approved drug for treating clinical depression, binds NLRP3 in silico, in vitro, and in vivo and inhibits activation of the NLRP3-ASC inflammasome and inflammatory cytokine release in RPE cells and macrophages, two critical cell types in dry AMD. We also demonstrate that fluoxetine, unlike several other antidepressant drugs, reduces Alu RNA–induced RPE degeneration in mice. Finally, by analyzing two health insurance databases comprising more than 100 million Americans, we report a reduced hazard of developing dry AMD among patients with depression who were treated with fluoxetine. Collectively, these studies identify fluoxetine as a potential drug-repurposing candidate for dry AMD.

Original languageEnglish (US)
Article numbere2102975118
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number41
DOIs
StatePublished - Oct 12 2021

Keywords

  • Fluoxetine
  • Health insurance databases
  • Macular degeneration
  • Molecular modeling
  • Retina

ASJC Scopus subject areas

  • General

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