Abstract
PurposeTo assess the neuroprotective effects of flibanserin (formerly BIMT-17), a dual 5-HT1A agonist and 5-HT2A antagonist, in a light-induced retinopathy model.MethodsAlbino 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.ResultsA 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.ConclusionsIntraperitoneal 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.
Highlights
Inherited retinal dystrophies (IRDs), such as retinitis pigmentosa, are clinically and genetically diverse, and account for approximately 5% of the vision loss in the Western world. [1,2,3] There are no effective treatments for most of these disorders, but gene therapy shows promise for a small subset of IRDs. [4,5,6,7,8] with almost 180 genes and thousands of distinct mutations, developing gene replacement strategies for all IRD patients will be a long and difficult endeavor. [2] The development of gene-independent therapies is essential in preserving retinal morphology and function until suitable gene therapies can be developed
Mechanistic data suggests that this effect is mediated through 5HT1A receptors and that flibanserin augments the expression of genes capable of reducing mitochondrial dysfunction and oxidative stress
Since flibanserin is already Food and Drug Administration (FDA)-approved for other indications, the potential to repurpose this drug for treating retinal degenerations merits further investigation
Summary
Inherited retinal dystrophies (IRDs), such as retinitis pigmentosa, are clinically and genetically diverse, and account for approximately 5% of the vision loss in the Western world. [1,2,3] There are no effective treatments for most of these disorders, but gene therapy shows promise for a small subset of IRDs. [4,5,6,7,8] with almost 180 genes and thousands of distinct mutations, developing gene replacement strategies for all IRD patients will be a long and difficult endeavor. [2] The development of gene-independent therapies is essential in preserving retinal morphology and function until suitable gene therapies can be developed. Recent studies conducted by our lab and others suggest that certain serotonin receptor agonists and antagonists provide neuroprotection against light-induced retinopathy. [15,16,17,18,19,20, 26] 5-HT1A receptor agonists, such as 8-OH-DPAT and AL-8309B, provided anti-oxidant protection against light-damage in albino rats and in a genetic mouse model for AMD. [15,16,17] 5-HT2A receptor antagonists, ketanserin and sarpogrelate, protected against light-induced retinopathy in albino Balb/c mice and in the Stargardt Abca4-/-Rdh8-/- mouse model. [20, 22, 27] Altogether, these reports suggest that 5-HT1A receptor agonists and 5-HT2A receptor antagonists can elicit neuroprotective effects in the retina and warrant their continued investigation as a therapeutic class in treatment of retinal degeneration. All mice were euthanized via gradual CO2 inhalation and cervical dislocation
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