The use of zebrafish for assessing ototoxic and otoprotective agents.
Zebrafish and other fish exhibit hair cells in the lateral-line neuromasts which are structurally and functionally similar to mammalian inner ear hair cells. To facilitate drug screening for ototoxic or otoprotective agents, we report a straightforward, quantitative in vivo assay to determine potential ototoxicity of drug candidates and to screen otoprotective agents in zebrafish larva. In this study, a fluorescent vital dye, DASPEI (2-(4-(dimethylamino)styryl)-N-ethylpyridinium iodide), was used to stain zebrafish hair cells in vivo and morphometric analysis was performed to quantify fluorescence intensity and convert images to numerical endpoints. Various therapeutics, including gentamicin, cisplatin, vinblastine sulfate, quinine, and neomycin, which cause ototoxicity in humans, also resulted in hair cell loss in zebrafish. In addition, protection against cisplatin-induced ototoxicity was observed in zebrafish larva co-treated with cisplatin and different antioxidants including, glutathione (GSH), allopurinol (ALO), N-acetyl l-cysteine (l-NAC), 2-oxothiazolidine-4-carboxylate (OTC) and d-methionine (d-MET). Our data indicate that results of ototoxicity and otoprotection in zebrafish correlated with results in humans, supporting use of zebrafish for preliminary drug screening.
Ton
Christopher
C
Phylonix Pharmaceuticals, Inc., 100 Inman St., Cambridge, MA 02139, USA.
Parng
Chuenlei
C
D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity; D000970:Antineoplastic Agents / Q000633:toxicity; D000975:Antioxidants / Q000494:pharmacology; D002945:Cisplatin / Q000633:toxicity; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D007758:Ear, Inner / Q000187:drug effects* / Q000473:pathology; D005456:Fluorescent Dyes; D005839:Gentamicins / Q000633:toxicity; D005978:Glutathione / Q000494:pharmacology; D006198:Hair Cells, Auditory / Q000187:drug effects / Q000473:pathology; D006801:Humans; D007814:Larva / Q000187:drug effects; D023421:Models, Animal; D011726:Pyridinium Compounds; D013045:Species Specificity; D015027:Zebrafish / Q000033:anatomy & histology*
D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D000975:Antioxidants; D005456:Fluorescent Dyes; D005839:Gentamicins; D011726:Pyridinium Compounds; C025042:2-(dimethylaminostyryl)-1-ethylpyridinium; D005978:Glutathione; D002945:Cisplatin