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

Abstract

The atrophic form of age-related macular degeneration (dry AMD) affects nearly 200 million people worldwide. There is no FDA-approved therapy for this disease, which is the leading cause of irreversible blindness among people over 50 years 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 that it inhibits activation of the NLRP3-ASC inflammasome in RPE cells and macrophages, two critical cell types in dry AMD. We also demonstrate that fluoxetine, unlike several other anti-depressant 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 triangulate to link fluoxetine as a potential drug repurposing candidate for a major unmet medical need that causes blindness in millions of people in the United States and across the world.Significance StatementDry age-related macular degeneration (AMD) affects the vision of millions of people worldwide. There is currently no FDA-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 the assembly and activation of the NLRP3-ASC inflammasome. As a result, it also blocks the degeneration of retinal pigmented epithelium (RPE) cells in an animal model of dry AMD. Furthermore, we demonstrate through an analysis of health insurance databases that use of this FDA-approved anti-depressant drug is associated with reduced incidence of dry AMD. These studies identify that fluoxetine is a potential repurposing candidate for AMD, a prevalent cause of blindness.

Fluoxetine degrades luminance perceptual thresholds while enhancing motivation and reward sensitivity

“…Fluoxetine hydrochloryde is a SSRI which binds to the human 5-HT transporter with a Ki of 0.9 nmol/l and is between 150- and 900-fold selective over 5-HT1A, 5-HT2A, 5-HT2c, H1, α1, α2-adrenergic, and muscarinic receptors (Ambati et al, 2021). The fluoxetine (N-Methyl-3-[(4-trifluoromethyl) phenoxy]-3-phenylpropylamine hydrochloride) used in the present study has a molecular weight of 345,78 g/mol.…”

NLRP3-Dependent Pyroptosis: A Candidate Therapeutic Target for Depression

“…NLRP3 inflammasome activation drives the progression of depression and is detrimental to post-stress recovery (Pandey et al, 2021;Yang et al, 2021). Fluoxetine, a clinical antidepressant licensed by the Food and Drug Administration, has been found to bind and inhibit NLRP3-ASC inflammasome (Ambati et al, 2021). In cigarette smoke-induced chronic obstructive pulmonary disease (COPD) and depression mouse models, cigarette smoke-induced glucocorticoid resistance was associated with NLRP3 inflammasome activation-induced inflammatory cascade responses.…”

The learning curve of murine subretinal injection among clinically trained ophthalmic surgeons

“…Successful subretinal delivery of Alu RNA results in RPE degeneration evident after 7 days. 13,14,[16][17][18][19]27 Prior to commencing subretinal injection training, all three trainees had completed three-year surgical residency programs in ophthalmology with experience in microsurgeries in people.…”