Retinal Toxicity Induced by the Administration of a Pan–Cyclin Dependent Kinase (cdk) Inhibitor in Albino Mice

Abstract

Abstract: : Purpose: In this poster presentation we report unexpected retinal toxicity in the eyes of mice treated with a pan–cyclin–dependent kinase inhibitor.Cyclin–dependent kinases (Cdks) are core components of the cell cycle machinery that govern the transition between phases during cell cycle progression. Since deregulated cdk activity is a hallmark of malignancy, these enzymes are considered promising targets for cancer therapy. Methods:This particular CDK inhibitor was administered intravenously to CD–1 mice, at a dose of 50 mg/kg/day for 5 consecutive days. A group of treated mice were euthanized 24 hours after the last dose (study day 6), and a second group after a 21–day drug–free recovery period (study day 26). Results:Microscopic findings in the eyes of compound –treated mice were only detected after the recovery period. Retinal changes were characterized by a decrease in the thickness and cellularity of the outer layers of the retina, mainly the photoreceptor and outer nuclear cell layers. Although light microscopy examination of mice euthanized on day 6 revealed no morphologic evidence of retinal toxicity, apoptotic retinal cells were detected using a TUNEL assay (Apop Tag Kit, Intergen). Conclusions: The pathogenesis of the ocular lesions is unclear; however, retinal toxicity may be mechanistically driven since compound accumulation was detected within the eyes of treated animals and cdk5 is known to play a significant role in phototransduction and retinal development.

Keywords: retinal degenerations: cell biology • retina: distal (photoreceptors, horizontal cells, bipolar cells) • pathobiology