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Retinal Neuroprotective Effects of Flibanserin, an FDA-Approved Dual Serotonin Receptor Agonist-Antagonist
Aaron S Coyner1, Renee C Ryals1, Cristy A Ku1
1Casey Eye Institute, Oregon Health & Science University, Portland, Oregon, United States of America.
Purpose:
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.
Insights
Flibanserin demonstrates neuroprotective effects in a mouse model of light-induced retinopathy. This drug preserves retinal structure and function, suggesting potential for treating retinal degenerations.
Area of Science:
- Ophthalmology
- Neuroscience
- Pharmacology
Background:
- Light-induced retinopathy is a model for retinal degeneration.
- Flibanserin is a dual 5-HT1A agonist and 5-HT2A antagonist.
- Investigating novel therapeutic agents for retinal diseases is crucial.
Purpose of the Study:
- To assess the neuroprotective effects of flibanserin in a light-induced retinopathy mouse model.
- To determine the role of 5-HT1A receptors in flibanserin's neuroprotective action.
- To explore the molecular mechanisms underlying flibanserin's therapeutic potential.
Main Methods:
- Mice were treated with varying doses of flibanserin or vehicle.
- 5-HT1A antagonist (WAY 100635) and 5-HT1A knockout mice were used to assess receptor involvement.
- Retinal structure and function were evaluated using OCT and electroretinography.
- Gene expression analysis (RT-qPCR) was performed to investigate mechanisms.
Main Results:
- Flibanserin dose-dependently preserved outer retinal structure and function.
- Both single-day and five-day treatment regimens showed significant protection.
- Neuroprotection was dependent on 5-HT1A receptor activity.
- Flibanserin increased the expression of genes involved in reducing oxidative stress and mitochondrial dysfunction.
Conclusions:
- Flibanserin exhibits significant neuroprotective effects in a light-induced retinopathy model.
- The protective mechanism is mediated via 5-HT1A receptors.
- Flibanserin may be a promising candidate for repurposing to treat retinal degenerations due to its FDA approval and demonstrated efficacy.
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