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F.M. Richards, G. Kimber, P. Butler, G. Waldron, T. Knight, P. Goldsmith, A.L. Fleming; Prediction Of Ophthalmic Effects In Man By Screening Drugs For The Optokinetic And Optomotor Responses In Zebrafish . Invest. Ophthalmol. Vis. Sci. 2006;47(13):2622.
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The zebrafish retina is similar to the human retina in structure and function and therefore is potentially a good model system in which to study the effect of drugs on vision. The purpose of this study was to assess the predictivity of the zebrafish system.
The Optomotor and Optokinetic Responses (OMR and OKR) have been well characterised in zebrafish (e.g. Neuhauss et al J. Neurosci. 19; 8603 (1999), Rinner et al IOVS 46; 137 (2005)). We have now developed OMR and OKR assay systems to enable screening of small amounts of compound by immersion of groups of zebrafish larvae in a 24–well plate system, allowing for a more cost–effective and higher throughput test system than the current mammalian assays.
This assay has been validated by using (i) ethambutol (ETB) which can cause optic neuropathy in man and inhibits retinal ganglion cell function in fish; and (ii) 2–amino–4–phosphonobutyric acid (APB), which inhibits retinal ganglion cells’ ON responses and the ERG b–wave in mammals and zebrafish. Both ETB and APB inhibited OMR and OKR after chronic immersion of zebrafish larvae. Inhibition of OMR and OKR by acute treatment with APB was reversible. Testing the predictivity of this system by blinded screening of a set of 10 drugs that have been reported to cause effects on vision in man (some with very mild effects, some severe), has shown very good correlation with 80% predictivity. The two drugs, which did not correlate cause visual disturbance through their effects on pupillary constriction and accommodation, neither of which phenomena are present in zebrafish.
We conclude that this validates the use of zebrafish in predicting potential visual effects much earlier in the drug discovery process than is currently possible.
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