Single Doses of a New Vitamin A Derivative (AG-787-14-1) Selectively Slow Down Rod Visual Cycle in Rats

Abstract

Purpose: : To quantify the effect and test the reversibility of a single dose of a new vitamin A derivative (AG-787-14-1) on retinal function in rats.

Methods: : A total of 36 Brown Norway rats were assigned either into a control group (vehicle injected) (n=13), or in one of 3 groups treated with single dose intra-peritoneal application of AG-787-14-1 either at 20 (n=8); 5 (n=7) or 1 mg/kg (n=8). Evaluations were performed at baseline and 12 hours after treatment by means of Ganzfeld ERGs. Intensity-response relationship of b-wave amplitude was evaluated at scotopic conditions by applying white stimuli (0.00003 to 0.3 cd.s/m²). Fast dynamics of rod sensitivity was assessed by a paired-flash paradigm (100 to 4000 ms apart). Additionally, the recovery of b-wave amplitude after exposure to bleaching light (400 cd/m² for 30 s) was evaluated for 70 min with a double flash every 2 minute (0.003 and 10 cd.s/m²; ISI= 1 sec.). Subsequently, photopic ERGs were recorded after 10 min of light adaptation.

Results: : No effects were found either on fully dark-adapted sensitivity or on fast recovery after rod desensitization. In contrast, drug treatment markedly delayed rod recovery from 60 min after bleaching on: at 20 mg/kg b-wave amplitude was 53.9 % lower compared to baseline (p<0.05); and at 5 mg/kg it was 22.2 % lower (p<0.05). Recovery rates were normal 8 weeks after treatment. Light adapted ERG amplitudes showed no changes.

Conclusions: : Treatment with AG-787-14-1 resulted in specific and reversible delay in the recovery of dark adaptation after bleaching in rats. This compound may have therapeutic implications for some forms of retinal and macular degeneration associated with accumulation of biosynthetic intermediates of the visual cycle.

Keywords: retinal degenerations: cell biology • electroretinography: non-clinical • retinal pigment epithelium