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Robert J. Collier, Yamini Patel, Elizabeth A. Martin, Olga Dembinska, Mark Hellberg, D. Scott Krueger, Michael A. Kapin, Carmelo Romano; Agonists at the Serotonin Receptor (5-HT1A) Protect the Retina from Severe Photo-Oxidative Stress. Invest. Ophthalmol. Vis. Sci. 2011;52(5):2118-2126. doi: 10.1167/iovs.10-6304.
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5-HT1A agonists are neuroprotective in CNS injury models. The authors evaluated the efficacy of 5-HT1A agonists to protect the retina from severe blue light–induced photo-oxidative damage.
Albino rats were dosed (subcutaneously) with AL-8309A, 8-OH DPAT, or buspirone once or three times before 6-hour exposure to blue light. Electroretinograms (ERGs) were measured to assess retinal function, and retinal damage was evaluated by light microscopy. Topical ocular dosing with 1.75% AL-8309B was also evaluated. Rats were dosed with WAY-100635, a 5-HT1A antagonist, to determine whether protection required activation of the 5-HT1A receptor.
ERG response amplitudes were significantly (P < 0.05) depressed more than 66% in vehicle-dosed rats after light exposure. ERGs were significantly higher in rats treated with AL-8309A (0.1–30 mg/kg), 8-OH DPAT (0.1–1 mg/kg), buspirone (5–20 mg/kg) or topical ocular with 1.75% AL-8309B. Retinas from AL-8309A and 8-OH DPAT–treated rats were devoid of histologic lesions. Significant protection was measured in rats dosed once 0, 24, or 48 hours before light exposure. Protection provided by dosing with AL-8309B or 8-OH DPAT was inhibited in rats predosed with WAY-100635.
5-HT1A agonists provided potent and complete functional and structural protection. Protection was inhibited by treatment with WAY-100635, confirming the requirement for activating the 5-HT1A receptor in initiating this survival pathway. Single-dose experiments with AL-8309A suggest that the mechanism of protection is rapidly activated and protection persists for 48 hours. AL-8309B (1.75%) was effective after topical ocular dosing. AL-8309B is under evaluation in the clinic and may be useful in treating age-related macular degeneration.
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