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R. Collier, E. Martin, R. Landers, C. Cully, Y. Patel, S. Krueger; Prevention of Photic-Induced Retinopathy with 8-OH-DPAT . Invest. Ophthalmol. Vis. Sci. 2003;44(13):5246.
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Purpose: Eliprodil (AL-4043), a potent NMDA antagonist, has been shown to protect retinal photoreceptors from oxidative injury. In this study, the potency of AL-4043 and its R (AL-4822) and S (AL-4821) isomers were compared to receptor binding data to elucidate potential mechanisms of protection. Based on the efficacy and receptor binding profiles of these molecules, 5-HT1A agonist activity was evaluated. Methods: Albino rats were dosed (IP) with eliprodil or its isomers (0 to 80 mg/kg) 48, 24 and 0 hrs prior to a 6-hr blue-light exposure (220fc). ERGs were measured after a 5-day recovery period. Additionally, rats were dosed with a 5-HT1A agonist, 8-OH-DPAT (0, 0.5, and 1.0 mg/kg), prior to light exposure. Retinal function was assessed after a 5-day recovery period. Retinal lesions were evaluated 3 weeks later. Results: Compared to normals, ERG responses from vehicle-dosed light-exposed rats were significantly depressed (70%). Significant protection of retinal function was measured with AL-4821 (10 mg/kg), AL-4043 (20 mg/kg) and AL-4822 (40 mg/kg). Binding affinity (IC50, nM) for the NMDA receptor was >10,000 (S-), 380 (R,S-) and 320 (R-isomer). At the 5-HT1A receptor, the IC50s (nM) were 111, 191, and 1840, respectively. Treatment with 8-OH-DPAT resulted in significant preservation of retinal function and structure in rats dosed with 1 mg/kg. ERG a-wave response amplitudes were 50% of normal and the ONL was significantly thicker compared to vehicle dosed rats and not different from normal. Conclusions: The neuroprotective activity measured with eliprodil and its isomers did not follow its binding efficacy to the NMDA receptor; however, its activity appeared to be related to its binding affinity to the 5-HT1A receptor. Treatment with a 5-HT1A agonist demonstrated marked potency and suggests a novel approach to treatment of retinal disease.
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