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Alfred S Lewin, Chulbul M Ahmed, Haoyu Mao, Hong Li; A 5HT1a Agonist Stimulates an Antioxidant Response and Protects the Retina in a Mouse Model of Geographic Atrophy. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):4202.
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Reactive oxygen species derived from mitochondria may initiate RPE and photoreceptor damage in age related macular degeneration (AMD). The purpose of this project was to test the efficacy of 8-OH-DPAT in a mouse model of geographic atrophy based on deletion of Sod2 in the retinal pigment epithelium (RPE).
ARPE-19 cells were challenged with an oxidative stressor plus and minus the 5HT1a agonist, 8-OH-DPAT. They were tested for survival and for production of protective enzymes. Mice in which the gene for Mn-superoxide dismutase was deleted in the RPE were treated by daily injection of 8-OH-DPAT for 4 months, and retinal structure and function were monitored by SD-OCT and ERG. Optokinetic measurement was used to assess vision and light and electron microscopy were used to evaluate tissues.
In ARPE-19 cells, 8-OH-DPAT treatment stimulated Mt1, Nqo1 and Sod2 expression and provided a dose-dependent protection against the paraquat-induced cell death. Daily treatment of mice with 5 mg/kg of the drug, blocked the decrease in ERG amplitudes associated with this model of retinal degeneration and prevented structural damage to the RPE and photoreceptors. Marginal improvement in visual acuity was also measured following drug treatment.
When delivered systemically, this class of serotonin receptor agonists can protect the retina and RPE from oxidative stress that is thought to be a contributing factor to development of AMD.
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