Ocular safety assessment of sodium iodate in cynomolgus monkeys

Although sodium iodate (NaIO 3 )-induced retinal injury model has been widely used in rodents, its application in large animal species has encountered variation in retinal toxicity. NaIO 3 induced retinal degeneration and functional changes in sheep, but not in swine. In monkeys, administration of N...
Ausführliche Beschreibung

Although sodium iodate (NaIO 3 )-induced retinal injury model has been widely used in rodents, its application in large animal species has encountered variation in retinal toxicity. NaIO 3 induced retinal degeneration and functional changes in sheep, but not in swine. In monkeys, administration of NaIO 3 via a carotid artery affected only the cell function of ipsilateral retinal pigment epithelium. The aim of the present study was to identify the dosage and route of NaIO 3 administration resulting in morphologic and functional retinal changes in cynomolgus monkeys. Separate groups of animals received NaIO 3 intravenously in three different dosing paradigms. Vehicle control animals received phosphate-buffered saline. At selected time points following dosing, flash electroretinograms (ERGs) were recorded followed by necropsy. The eyes were examined microscopically post-necropsy and the levels of circulating microRNA-183 cluster were evaluated in the blood samples collected on days 1, 4, and 5 postdose. A statistically significant reduction in both scotopic a-wave and scotopic and photopic b-wave signals ( p < 0.05) were observed between the ERG signals acquired from NaIO 3 -treated and vehicle control animals, coupled with time-dependent elevations in plasma miR-183 cluster. Mild to moderate retinal degeneration was observed in the outer layer of the retina, which correlated well with the functional and clinical observations. There were no statistically significant differences in scotopic oscillatory potentials. These findings suggest that intravenous injection of sublethal NaIO 3 markedly damaged the cone and rod photoreceptors both functionally and morphologically, and plasma miR-183 reflected the retinal toxicity in those animals with moderate retinal damage. Ausführliche Beschreibung