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R. J. Collier, O. Dembinska, C. Cully-Adams, E. Martin, H. Hoang, C. Romano; Inhibition of Retinal Protection by AL-8309B, A 5-HT1A AGONIST, With WAY 100635, a 5-HT1A Antagonist, in the Rat Photo-Oxidative Injury Model. Invest. Ophthalmol. Vis. Sci. 2010;51(13):3327.
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Exposure of rats to blue light results in significant retinal lesions. The 5-HT1A agonists, AL-8309B and 8-OH DPAT completely ameliorated these lesions. The goal of this experiment was to determine if the retinoprotective activity measured with 5-HT1A agonists requires activation of the 5-HT1A receptor. This was determined by pre-dosing rats with a 5-HT1A antagonist, WAY 100635, prior to dosing with AL-8309B or 8-OH DPAT.
To determine the dose that protected retinal function by 50% to be used in the 5-HT1A agonist/ antagonist experiment, albino rats were dosed once with vehicle, 8-OH DPAT (0.05 - 0.5 mg/kg) or AL-8309B (0.1-30 mg/kg) SQ immediately prior to a 6-hr blue-light exposure. Photo-oxidative induced lesions were generated by exposure to blue light (3.1 X 103 mW/cm2). ERGs were measured to assess retinal function 5 days after light exposure. In the 5-HT1A agonist/antagonist experiment, rats were dosed with vehicle, 5-HT1A agonist, 5-HT1A agonist + Way 100635, or WAY 100635. Rats were dosed once with WAY 100635 thirty minutes before light exposure and/or were dosed with 5-HT1A agonist once immediately before light exposure began.
Five days after light exposure, ERG a- and b-wave responses from vehicle-dosed light-exposed rats were significantly (p<0.05) depressed compared to controls. ERGs recorded from rats dosed once with 8-OH DPAT (0.1 - 0.5 mg/kg) or AL-8309B (1- 30 mg/kg) were significantly protected (p<0.05) from this photo-oxidative induced retinopathy. Protection provided by dosing with 8-OH DPAT (0.5 mg/kg) was inhibited in rats predosed with the 5-HT1A antagonist, WAY 100635 (0.5 and 5 mg/kg). ERGs recorded from rats dosed once with WAY 100635 (5 mg/kg) 30 minutes prior to dosing with 8-OH DPAT and light exposure were not significantly (p>0.05) higher than ERG responses from vehicle-dosed rats. Similarly, protection provided by dosing with AL-8309B (1 mg/kg) was significantly inhibited in rats predosed with WAY 100635 (1 and 10 mg/kg).
ERGs recorded from rats dosed once with AL-8309B or 8-OH DPAT immediately before light exposure were significantly protected (p<0.05) from photo-oxidative induced retinopathy. This indicates that the mechanism of protection is activated quickly in this model. This protection was inhibited by treatment with a 5-HT1A antagonist, WAY 100635, demonstrating the requirement of activating the 5-HT1A receptor in initiating this survival pathway.
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