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

Extended bright light exposure after complete dark-adaptation results in retinal degeneration and reduced retinal function in albino BALB/c mice. The brightness and duration of light exposure have varied in previous studies, but the outcome consistently induces severe thinning of the outer nuclear layer and reduced photoreceptor function.1–9 Due to the acute, quantifiable degeneration observed after bright light exposure, light-induced retinopathy has been utilized as a screening tool for potential therapies that can protect the retina from outer retinal degeneration. Multiple studies using light-induced retinopathy models have stratified the potential efficacy of neuroprotective agents.1–9 Serotonin (5-hydroxytryptamine or 5-HT) is an ancient neurotransmitter that is closely regulated in the mammalian retina by a combination of limited production and aggressive uptake.10–14 Currently, there are seven known 5-HT receptor families (5-HT1 to 5-HT7), which have further been divided into subtypes based on specific molecular properties. Thus far, at least 17 subtypes have been described.15 The role of serotonin in the retina is not fully understood, but recent studies suggest that certain serotonin receptor agonists and antagonists can elicit neuroprotective effects.16–20 For example, Collier et al.16 showed that two 5-HT1A receptor agonists, 8-OH-DPAT and AL-8309B, can completely protect albino rat retinas, both structurally and functionally, from blue light-induced photo-oxidative damage. In addition, Chen et al.20 demonstrated that a 5-HT2A receptor antagonist, ketanserin, could protect the morphology of Abca4−/−Rdh8−/− mouse retinas from light-induced all-trans-retinal-mediated photoreceptor degeneration. Sarpogrelate hydrochloride, marketed as ANPLAG, is a 5-HT2A receptor antagonist that has been used to treat patients with peripheral arterial disease in Japan, China, and South Korea.21,22 Sarpogrelate was found to prevent thrombus formation in an experimental thrombosis mouse model, and a clinical pharmacologic study has shown that it inhibits platelet aggregation in patients with ischemic stroke.21,22 Inoue-Matsuhisa et al.23 investigated sarpogrelate's neuroprotective effects on an in vitro glutamate–induced retinal ganglion cell death model and an in vivo rat retinal ischemia model. A 30 mg/kg dose of sarpogrelate was able to partially protect rat retinas, both structurally and functionally, from inner retinal ischemia.23 Because sarpogrelate has an established safety profile in humans and has shown potential as a neuroprotective agent for the inner retina, we wanted to further investigate sarpogrelate's ability to protect the outer retina in a light-induced retinopathy model, which would establish sarpogrelate as a potential candidate for treating outer retinal degeneration. The present study aimed to determine if sarpogrelate, a selective 5-HT2A receptor antagonist, could protect the retina from light-induced retinopathy. A dose escalation study was performed and two treatment regimens were evaluated. To explore the potential for additive effects of different serotonin receptor modulators, a subtherapeutic dose of sarpogrelate—a 5-HT2A antagonist—was administered with a subtherapeutic dose of 8-OH-DPAT, a 5-HT1A agonist. Neuroprotection was characterized by preservation of retinal thickness, measured by spectral-domain optical coherence tomography (SD-OCT), and functional preservation, measured by ERG.