Sarpogrelate, a 5-HT2A Receptor Antagonist, Protects the Retina From Light-Induced Retinopathy

Abstract

Purpose: To determine if sarpogrelate, a selective 5-HT2A receptor antagonist, is protective against light-induced retinopathy in BALB/c mice.

Methods: BALB/c mice were dosed intraperitoneally with 5, 15, 30, 40, or 50 mg/kg sarpogrelate 48, 24, and 0 hours prior to bright light exposure (10,000 lux) as well as 24 and 48 hours after exposure. Additionally, a single injection regimen was evaluated by injecting mice with 50 mg/kg sarpogrelate once immediately prior to light exposure. To investigate the potential for additive effects of serotonin receptor agents, a combination therapy consisting of sarpogrelate (15 mg/kg) and 8-OH-DPAT (1 mg/kg) was evaluated with the 5-day treatment regimen. Neuroprotection was characterized by the preservation of retinal thickness and function, measured by spectral-domain optical coherence tomography (SD-OCT) and electroretinography (ERG), respectively.

Results: Mice that were light damaged and injected with saline had significantly reduced outer retinal thickness, total retinal thickness, and ERG amplitudes compared with naïve mice. A 5-day administration of 15, 30, or 40 mg/kg of sarpogrelate was able to partially protect retinal morphology and full protection of retinal morphology was achieved with a 50 mg/kg dose. Both 15 and 30 mg/kg doses of sarpogrelate partially preserved retinal function measured by ERG, whereas 40 and 50 mg/kg doses fully preserved retinal function. Additionally, a single administration of 50 mg/kg sarpogrelate was able to fully preserve both retinal morphology and function. Administration of 15 mg/kg of sarpogrelate and 1 mg/kg of 8-OH-DPAT together demonstrated an additive effect and fully preserved retinal morphology.

Conclusions: A 5- or 1-day treatment with 50 mg/kg sarpogrelate can completely protect the retina of BALB/c mice from light-induced retinopathy. Partial protection can be achieved with lower doses starting at 15 mg/kg and protection increases in a dose-dependent manner. Treatment with low doses of sarpogrelate and 8-OH-DPAT elicits an additive effect that results in full protection of retinal morphology.

Figure 1

Sarpogrelate protects retinal morphology in a dose-dependent manner. Representative linear SD-OCT scans of nasal retina from a naïve mouse or mice injected with either 50, 40, 30, 15, or 5 mg/kg of sarpogrelate or saline. Injections followed the 5-day time course with a 6-hour light damage.

Figure 2

Sarpogrelate elicits neuroprotective effects in a dose-dependent manner. (A) Receptor plus thicknesses and total retinal thicknesses obtained from segmented horizontal SD-OCT scans were averaged and plotted versus retinal eccentricity from the optic nerve head. The gray area indicates ±2 SD of the naïve averaged data. The correlation coefficient, r, was determined by comparing right eye REC+ thicknesses to the dose of sarpogrelate administered. (B) Electroretinogram a- and b-wave amplitudes from mice in each group were extracted from individual waveforms, averaged and plotted versus the light intensity of each flash. Averages are represented as mean ± standard error. “V” indicates at which light intensity the statistical analysis was performed. The correlation coefficient, r, was determined by comparing each animal's a_max amplitude to the dose of sarpogrelate administered. Three animals died after acquiring OCT images, but prior to ERG recordings. Injections followed the 5-day time course with a 6-hour light damage. Black: Naïve. Red: 50 mg/kg sarpogrelate. Yellow: 40 mg/kg sarpogrelate. Purple: 30 mg/kg sarpogrelate. Green: 15 mg/kg sarpogrelate. Blue: 5 mg/kg sarpogrelate. Gray: Saline.

Figure 3

A 1-day time course of 50 mg/kg sarpogrelate completely protects retinal morphology and function. Receptor plus thicknesses (A) and total retinal thicknesses (B) obtained from segmented horizontal SD-OCT scans were averaged and plotted versus retinal eccentricity from the optic nerve head. The gray area indicates ±2 SD of the naïve averaged data. Electroretinogram a- (C) and b-wave (D) amplitudes for all mice in each group were extracted from individual waveforms, averaged and plotted versus the light intensity of each flash. Averages are represented as mean ± standard error. “V” indicates at which light intensity the statistical analysis was performed. Black: Naïve. Red: 50 mg/kg 1-day time course. Blue: 50 mg/kg 5-day time course. Gray: Saline.

Figure 4

Chemical 8-OH-DPAT elicits neuroprotective effects in BALB/c mice. (A) Receptor plus thicknesses and total retinal thicknesses obtained from segmented horizontal SD-OCT scans were averaged and plotted versus retinal eccentricity from the optic nerve head. The gray area indicates ±2 SD of the naïve averaged data. (B) Electroretinogram a- and b-wave amplitudes from mice in each group were extracted from individual waveforms, averaged, and plotted versus the light intensity of each flash. Averages are represented as mean ± standard error. “V” indicates at which light intensity the statistical analysis was performed. One animal died after acquiring OCT images, but prior to ERG recordings. Injections followed the 5-day time course with a 1-hour light damage. Black: Naïve. Red: 10 mg/kg 8-OH-DPAT. Blue: 1 mg/kg 8-OH-DPAT. Gray: Saline.

Figure 5

A combination therapy of sarpogrelate and 8-OH-DPAT provide additive neuroprotection. (A) Receptor plus thicknesses and total retinal thicknesses obtained from segmented horizontal SD-OCT scans were averaged and plotted versus retinal eccentricity from the optic nerve head. The gray area indicates ±2 SD of the naïve averaged data. (B) Representative linear SD-OCT scans. (C) Electroretinogram a- and b-wave amplitudes from mice in each group were extracted from individual waveforms, averaged and plotted versus the light intensity of each flash. Averages are represented as mean ± standard error. “V” indicates at which light intensity the statistical analysis was performed. Injections followed the 5-day time course with a 1-hour light damage. Black: Naïve. Green: 8-OH-DPAT + Sarpogrelate. Blue: 1 mg/kg 8-OH-DPAT. Red: 15 mg/kg Sarpogrelate. Gray: Saline.