Early safety assessment of human oculotoxic drugs using the zebrafish visualmotor response

Introduction: Many prescribed drugs can adversely affect the eye by causing damage to the function of visual pathways or toxicity to the retina. Zebrafish have the potential to efficiently predict drugs with adverse ocular effects at pre-clinical stages of development. In this study, we explore the potential of using a semi-automated visual behaviour assay to predict drug-induced ocular toxicity in wild-type zebrafish larvae. Methods: 3 dpf larvae were treated with six known oculotoxic drugs and five control drugs in embryo medium containing 0.1% DMSO. After 48 h, larvae were assessed using the visualmotor response (VMR), an assay which quantifies locomotor responses to light changes; the optokinetic response (OKR), a behavioural assay that quantifies saccadic eye responses to rotating stimuli; and the touch response, a locomotor response to tactile stimuli. Results: 9 of 10 negative control drugs had no effect on zebrafish visual behaviour. 5 of the 6 known oculotoxic drugs (digoxin, gentamicin, ibuprofen, minoxidil and quinine) showed adverse effects on zebrafish visual behaviour assessed by OKR or the more automated VMR. No gross morphological changes were observed in treated larvae. The general locomotor activity of treated larvae, tested using the touch response assay, showed no differences with respect to controls. Overall the VMR assay had a sensitivity of 83%, a specificity of 100% and a positive predictive value of 100%. Discussion: This study confirms the suitability of the VMR assay as an efficient and predictive pre-clinical approach to evaluate adverse ocular effects of drugs on visual function in vivo.