Retinal Neuroprotective Effects of Flibanserin, an FDA-Approved Dual Serotonin Receptor Agonist-Antagonist

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.

A Mouse Model of Retinal Recovery From Photo-Oxidative/Photo-Inflammatory Injury: Nrf2, SOD1, DJ-1, and Parkin Are Not Essential to Recovery

“…These observations parallel similar findings described in primates. Furthermore, while we and others have shown that the oxidative stress response is very important in the acute injury phase, [1][2][3][4][5][6][7][8][9][27][28][29][30] we have also demonstrated that mice lacking oxidative stress response enzymes (SOD1, DJ-1, and Parkin) or the oxidative stress response master regulator Nrf2-despite suffering increased acute injury-still show significant recovery after the initial injury. This suggests that classic oxidative stress response pathways are not essential for retinal recovery after injury.…”

“…A great deal of interest has been devoted to the important topic of understanding the mechanisms of acute retinal injury and developing strategies to protect photoreceptors from acute injury. [1][2][3][4][5][6][7][8][9] However, in many human retinal diseases, the damage involves repetitive sub-lethal stressors. In fact, by the time of diagnosis, such damage has often already started or may be difficult to completely avoid.…”

The Role of ERK1/2 Activation in Sarpogrelate-Mediated Neuroprotection

“…At 11:00 AM, 2 hours after the start of the dark cycle, mice were administered an intraperitoneal injection of 25 mg/kg sarpogrelate (dissolved in saline) (Tocris Bioscience, Bristol, UK) or equivalent volume of saline immediately before 1 hour of bright light exposure (LE). 10 , 11 For MEK inhibitor experiments, mice were administered an intraperitoneal injection of 5 mg/kg PD0325901 (dissolved in distilled water with 1% dimethyl sulfoxide) (SelleckChem, Houston, TX, USA) or vehicle 15 minutes before sarpogrelate or saline injection. After LE, mice were returned to the dark until the appropriate time of retinal harvest, or returned back to the 12-hour alternating light/dark cycle room for future in vivo imaging and electrophysiology studies.…”

“…A custom light box was built for the induction of retinopathy. 10 , 11 It was able to hold up to 16 mice and produced approximately 10,000 lux of uniform light. After 2 hours of dark adaptation, albino BALB/c mice were exposed to 1 hour of light emitted by four compact fluorescent lamps (42 watts, 6500 K color temperature), which give off fluorescent white light having an emission spectrum similar to daylight.…”

“…Increasing evidence suggests that multiple G protein (guanine nucleotide–binding protein)–coupled receptors (GPCRs) are expressed in the retina and modulation of these receptors can protect the retina from outer retinal degeneration. 6 – 12 A retinal transcriptome analysis has demonstrated expression of serotonergic (5-HT), adrenergic, and dopaminergic GPCRs in the mammalian retina. 6 Activation and inhibition of these common GPCRs are known to modulate diverse secondary pathways including adenylyl cyclase, small GTPase Ras homologs, phospholipase C (PLC), and regulation of ion channels, which are important for regulating cellular functions including metabolism, growth, proliferation, survival, transcription, and protein synthesis.…”