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 Baker, Kenneth M. Marion, Mehrdad Shadmehr, Cliff I. Stains, Brian C. Werner, Srinivas R. Sadda, Ethan Will Taylor, S. Scott Sutton, Joseph Magagnoli, Bradley D. Gelfand
Abstract
Significance Dry age-related macular degeneration (AMD) affects the vision of millions of people worldwide. There is currently no Food and Drug Administration–approved treatment for dry AMD. The inflammasome components NLRP3 and ASC have been implicated in the pathogenesis of dry AMD. We report that fluoxetine, which is approved for the treatment of clinical depression, directly binds the NLRP3 protein and prevents NLRP3-ASC inflammasome assembly and activation. Fluoxetine prevents the degeneration of retinal pigmented epithelium cells in an animal model of dry AMD. We also present evidence from a big data analysis of health insurance databases that fluoxetine use is associated with reduced risk of developing dry AMD. These studies identify a potential repurposing candidate for a prevalent cause of blindness.