Early safety assessment of human oculotoxic drugs using the zebrafish visualmotor response
Early safety assessment of human oculotoxic drugs using the zebrafish visualmotor response
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DOI：
10.1016/j.vascn.2013.09.002
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发表时间：
2014-01-01
影响因子：
1.9
通讯作者：
Kennedy, Breandan N.
中科院分区：
文献类型：
--
作者：
Deeti, Sudhakar;O'Farrell, Sean;Kennedy, Breandan N.
简介：许多处方药会损害视觉通路的功能或对视网膜产生毒性，从而对眼睛产生不利影响。斑马鱼有可能在临床前开发阶段有效地预测对眼睛有不良影响的药物。在这项研究中，我们探索了使用半自动视觉行为分析来预测药物对野生型斑马鱼幼体的眼毒性的可能性。方法：在含0.1%DMSO的胚胎培养液中，用6种已知眼毒药物和5种对照药物对3只DPF幼虫进行处理。48小时后，用视觉运动反应(VMR)、视动反应(OKR)和触觉反应(触觉反应)对幼虫进行了评估，视觉运动反应(VMR)是一种量化对光变化的运动反应的测试，视动反应(OKR)是一种量化眼球对旋转刺激的反应的行为测试。结果：10种阴性对照药物中有9种对斑马鱼的视觉行为无影响。已知的6种眼毒性药物(地高辛、庆大霉素、布洛芬、米诺地尔和奎宁)中有5种对斑马鱼的视觉行为有不良影响，通过OKR或更自动化的VMR进行评估。未观察到处理幼虫的大体形态变化。用触觉反应测试，处理幼虫的一般运动活动与对照没有差异。总体而言，VMR检测的敏感性为83%，特异性为100%，阳性预测值为100%。讨论：这项研究证实了VMR分析作为一种有效和可预测的临床前方法在体内评估药物对视觉功能的不良眼部影响是合适的。(C)2013 Elsevier Inc.保留所有权利。
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 inwild-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. (C) 2013 Elsevier Inc. All rights reserved.