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

Abstract

Publication informationJournal of Pharmacological and Toxicological Methods, 69 (1): 1-8 Publisher ElsevierItem record/more information http://hdl.handle.net/10197/7931 Publisher's statementThis is the author's version of a work that was accepted for publication in Journal of Pharmacological and Toxicological Methods. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Journal of Pharmacological and Toxicological Methods (VOL 69, ISSUE 1, ((2014) Abstract 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 druginduced 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 hours, 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.

Effects of the pharmaceutical contaminants ibuprofen, diclofenac, and carbamazepine alone, and in combination, on oxidative stress parameters in early life stages of tench (Tinca tinca)

“…Both COX isoforms as well as the synthesis of prostaglandins share a high similarity between humans and fish (David and Pancharatna 2009). The side-effects and toxicity of non-selective NSAIDs are well documented in mammals (Lascelles et al 2007;Khan and McLean 2012) and the negative influence of aquatic contaminants of this type are expected, and in some cases, have already been proven in nontarget aquatic organisms (Bhandari and Venables 2011;Deeti et al 2014).…”

Zebrafish—on the move towards ophthalmological research

“…However, this process is partly hindered due to a lack of predictive, convenient methods as well as the high expense associated with testing drug candidates in mammals. 63,114 For many years, researchers have been using zebrafish assays for drug toxicity screening with a view to provide early drug safety assessments. 115,116 So far, zebrafish have been used to predict drug-related cardiotoxicity, ototoxicity, developmental toxicity, neurotoxicity, oculotoxicity, and many more.…”

“…116 More recently, a study described zebrafish as a potential animal model to predict drug-related oculotoxicity at the preclinical stage. 114 In this study, 3 dpf zebrafish larvae were exposed to the known oculotoxic drugs (digoxin, gentamicin, ibuprofen, minoxidil, and quinine) for 48 h, and toxicity was assessed using visual behaviour. These drugs resulted in damage to visual function in zebrafish, thereby confirming the potential toxicity of these drugs to the human eye.…”

Transcriptional and Behavioral Responses of Zebrafish Larvae to Microcystin-LR Exposure

“…Moreover, the whole-animal behavioral responses can be measured effectively and characterize the sublethal exposure of fish to different molecules that is not accompanied by any obvious pathological effects [53]. Recently, the visual motor response (VMR) has been used for early safety assessment of oculotoxic drugs [54]. Therefore, our behavioral assay may be used to predict MCLR effects and to assess the toxicity risks.…”