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Retinal Neuroprotective Effects of Flibanserin, an FDA-Approved Dual Serotonin Receptor Agonist-Antagonist
PURPOSE: To assess the neuroprotective effects of flibanserin (formerly BIMT-17), a dual 5-HT(1A) agonist and 5-HT(2A) antagonist, in a light-induced retinopathy model. METHODS: Albino BALB/c mice were injected intraperitoneally with either vehicle or increasing doses of flibanserin ranging from 0.7...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Public Library of Science
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4957778/ https://www.ncbi.nlm.nih.gov/pubmed/27447833 http://dx.doi.org/10.1371/journal.pone.0159776 |
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author | Coyner, Aaron S. Ryals, Renee C. Ku, Cristy A. Fischer, Cody M. Patel, Rachel C. Datta, Shreya Yang, Paul Wen, Yuquan Hen, René Pennesi, Mark E. |
author_facet | Coyner, Aaron S. Ryals, Renee C. Ku, Cristy A. Fischer, Cody M. Patel, Rachel C. Datta, Shreya Yang, Paul Wen, Yuquan Hen, René Pennesi, Mark E. |
author_sort | Coyner, Aaron S. |
collection | PubMed |
description | PURPOSE: To assess the neuroprotective effects of flibanserin (formerly BIMT-17), a dual 5-HT(1A) agonist and 5-HT(2A) antagonist, in a light-induced retinopathy model. METHODS: Albino BALB/c mice were injected intraperitoneally with either vehicle or increasing doses of flibanserin ranging from 0.75 to 15 mg/kg flibanserin. To assess 5-HT(1A)-mediated effects, BALB/c mice were injected with 10 mg/kg WAY 100635, a 5-HT(1A) antagonist, prior to 6 mg/kg flibanserin and 5-HT(1A) knockout mice were injected with 6 mg/kg flibanserin. Injections were administered once immediately prior to light exposure or over the course of five days. Light exposure lasted for one hour at an intensity of 10,000 lux. Retinal structure was assessed using spectral domain optical coherence tomography and retinal function was assessed using electroretinography. To investigate the mechanisms of flibanserin-mediated neuroprotection, gene expression, measured by RT-qPCR, was assessed following five days of daily 15 mg/kg flibanserin injections. RESULTS: A five-day treatment regimen of 3 to 15 mg/kg of flibanserin significantly preserved outer retinal structure and function in a dose-dependent manner. Additionally, a single-day treatment regimen of 6 to 15 mg/kg of flibanserin still provided significant protection. The action of flibanserin was hindered by the 5-HT(1A) antagonist, WAY 100635, and was not effective in 5-HT(1A) knockout mice. Creb, c-Jun, c-Fos, Bcl-2, Cast1, Nqo1, Sod1, and Cat were significantly increased in flibanserin-injected mice versus vehicle-injected mice. CONCLUSIONS: Intraperitoneal delivery of flibanserin in a light-induced retinopathy mouse model provides retinal neuroprotection. Mechanistic data suggests that this effect is mediated through 5-HT(1A) receptors and that flibanserin augments the expression of genes capable of reducing mitochondrial dysfunction and oxidative stress. Since flibanserin is already FDA-approved for other indications, the potential to repurpose this drug for treating retinal degenerations merits further investigation. |
format | Online Article Text |
id | pubmed-4957778 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-49577782016-08-08 Retinal Neuroprotective Effects of Flibanserin, an FDA-Approved Dual Serotonin Receptor Agonist-Antagonist Coyner, Aaron S. Ryals, Renee C. Ku, Cristy A. Fischer, Cody M. Patel, Rachel C. Datta, Shreya Yang, Paul Wen, Yuquan Hen, René Pennesi, Mark E. PLoS One Research Article PURPOSE: To assess the neuroprotective effects of flibanserin (formerly BIMT-17), a dual 5-HT(1A) agonist and 5-HT(2A) antagonist, in a light-induced retinopathy model. METHODS: Albino BALB/c mice were injected intraperitoneally with either vehicle or increasing doses of flibanserin ranging from 0.75 to 15 mg/kg flibanserin. To assess 5-HT(1A)-mediated effects, BALB/c mice were injected with 10 mg/kg WAY 100635, a 5-HT(1A) antagonist, prior to 6 mg/kg flibanserin and 5-HT(1A) knockout mice were injected with 6 mg/kg flibanserin. Injections were administered once immediately prior to light exposure or over the course of five days. Light exposure lasted for one hour at an intensity of 10,000 lux. Retinal structure was assessed using spectral domain optical coherence tomography and retinal function was assessed using electroretinography. To investigate the mechanisms of flibanserin-mediated neuroprotection, gene expression, measured by RT-qPCR, was assessed following five days of daily 15 mg/kg flibanserin injections. RESULTS: A five-day treatment regimen of 3 to 15 mg/kg of flibanserin significantly preserved outer retinal structure and function in a dose-dependent manner. Additionally, a single-day treatment regimen of 6 to 15 mg/kg of flibanserin still provided significant protection. The action of flibanserin was hindered by the 5-HT(1A) antagonist, WAY 100635, and was not effective in 5-HT(1A) knockout mice. Creb, c-Jun, c-Fos, Bcl-2, Cast1, Nqo1, Sod1, and Cat were significantly increased in flibanserin-injected mice versus vehicle-injected mice. CONCLUSIONS: Intraperitoneal delivery of flibanserin in a light-induced retinopathy mouse model provides retinal neuroprotection. Mechanistic data suggests that this effect is mediated through 5-HT(1A) receptors and that flibanserin augments the expression of genes capable of reducing mitochondrial dysfunction and oxidative stress. Since flibanserin is already FDA-approved for other indications, the potential to repurpose this drug for treating retinal degenerations merits further investigation. Public Library of Science 2016-07-22 /pmc/articles/PMC4957778/ /pubmed/27447833 http://dx.doi.org/10.1371/journal.pone.0159776 Text en © 2016 Coyner et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Coyner, Aaron S. Ryals, Renee C. Ku, Cristy A. Fischer, Cody M. Patel, Rachel C. Datta, Shreya Yang, Paul Wen, Yuquan Hen, René Pennesi, Mark E. Retinal Neuroprotective Effects of Flibanserin, an FDA-Approved Dual Serotonin Receptor Agonist-Antagonist |
title | Retinal Neuroprotective Effects of Flibanserin, an FDA-Approved Dual Serotonin Receptor Agonist-Antagonist |
title_full | Retinal Neuroprotective Effects of Flibanserin, an FDA-Approved Dual Serotonin Receptor Agonist-Antagonist |
title_fullStr | Retinal Neuroprotective Effects of Flibanserin, an FDA-Approved Dual Serotonin Receptor Agonist-Antagonist |
title_full_unstemmed | Retinal Neuroprotective Effects of Flibanserin, an FDA-Approved Dual Serotonin Receptor Agonist-Antagonist |
title_short | Retinal Neuroprotective Effects of Flibanserin, an FDA-Approved Dual Serotonin Receptor Agonist-Antagonist |
title_sort | retinal neuroprotective effects of flibanserin, an fda-approved dual serotonin receptor agonist-antagonist |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4957778/ https://www.ncbi.nlm.nih.gov/pubmed/27447833 http://dx.doi.org/10.1371/journal.pone.0159776 |
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