title: Retinal Neuroprotective Effects of Flibanserin, an FDA-Approved Dual Serotonin Receptor Agonist-Antagonist.
abstract: OBJECTIVE
  To assess the neuroprotective effects of flibanserin (formerly BIMT-17), a dual 5-HT1A agonist and 5-HT2A 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-HT1A-mediated effects, BALB/c mice were injected with 10 mg/kg WAY 100635, a 5-HT1A antagonist, prior to 6 mg/kg flibanserin and 5-HT1A 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-HT1A antagonist, WAY 100635, and was not effective in 5-HT1A 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-HT1A 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.
authors.affiliation: Casey Eye Institute, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: Aaron S
authors.identifier: http://orcid.org/0000-0003-3261-1909
authors.initials: AS
authors.lastname: Coyner
authors.affiliation: Casey Eye Institute, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: Renee C
authors.initials: RC
authors.lastname: Ryals
authors.affiliation: Casey Eye Institute, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: Cristy A
authors.initials: CA
authors.lastname: Ku
authors.affiliation: Casey Eye Institute, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: Cody M
authors.initials: CM
authors.lastname: Fischer
authors.affiliation: Casey Eye Institute, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: Rachel C
authors.initials: RC
authors.lastname: Patel
authors.affiliation: Casey Eye Institute, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: Shreya
authors.initials: S
authors.lastname: Datta
authors.affiliation: Casey Eye Institute, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: Paul
authors.initials: P
authors.lastname: Yang
authors.affiliation: Baylor University Medical Center, Dallas, Texas, United States of America.
authors.forename: Yuquan
authors.initials: Y
authors.lastname: Wen
authors.affiliation: New York State Psychiatric Institute, Columbia University, New York, New York, United States of America.
authors.forename: René
authors.initials: R
authors.lastname: Hen
authors.affiliation: Casey Eye Institute, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Pennesi
mesh_terms: D000818:Animals; D000975:Antioxidants; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D001562:Benzimidazoles / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D004307:Dose-Response Relationship, Radiation; D004596:Electroretinography; D055786:Gene Knockout Techniques; D008027:Light / Q000009:adverse effects; D008297:Male; D051379:Mice; D018696:Neuroprotective Agents / Q000494:pharmacology*; D044282:Receptor, Serotonin, 5-HT1A / Q000235:genetics / Q000378:metabolism; D044402:Receptor, Serotonin, 5-HT2A / Q000235:genetics / Q000378:metabolism; D012160:Retina / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology / Q000528:radiation effects; D012164:Retinal Diseases / Q000175:diagnosis / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D018490:Serotonin Agents / Q000494:pharmacology*; D041623:Tomography, Optical Coherence
chemical_list: D000975:Antioxidants; D001562:Benzimidazoles; D018696:Neuroprotective Agents; D044402:Receptor, Serotonin, 5-HT2A; D018490:Serotonin Agents; D044282:Receptor, Serotonin, 5-HT1A; C098107:flibanserin