Identification of antiparkinsonian drugs in the 6-hydroxydopamine zebrafish model

Parkinson's disease (PD) is known as a movement disorder due to characteristic motor features. Existing therapies for PD are only symptomatic, and their efficacy decreases as disease progresses. Zebrafish, a vertebrate in which parkinsonism has been modelled, offers unique features for the identification of molecules with antiparkinsonian properties. Here, we developed a screening assay for the selection of neuroactive agents with antiparkinsonian potential. First, we performed a pharmacological validation of the phenotypes exhibited by the 6-hydroxydopamine zebrafish model, by testing the effects of known antiparkinsonian agents. These drugs were also tested for disease-modifying properties by whole mount immunohistochemistry to TH+ neurons and confocal microscopy in the dopaminergic diencephalic cluster of zebrafish. Next, we optimized a phenotypic screening using the 6-hydroxydopamine zebrafish model and tested 1600 FDA-approved bioactive drugs. We found that 6-hydroxydopamine-lesioned zebrafish larvae exhibit bradykinetic and dyskinetic-like behaviours that are rescued by the administration of levodopa, rasagiline, isradipine or amantadine. The rescue of dopaminergic cell loss by isradipine was also verified, through the observation of a higher number of TH+ neurons in 6-OHDA-lesioned zebrafish larvae treated with this compound as compared to untreated lesioned larvae. The phenotypic screening enabled us to identify several compounds previously positioned for PD, as well as, new molecules with potential antiparkinsonian properties. Among these, we selected stavudine, tapentadol and nabumetone as the most promising candidates. Our results demonstrate the functional similarities of the motor impairments exhibited by 6-hydroxydopamine-lesioned zebrafish with mammalian models of PD and with PD patients, and highlights novel molecules with antiparkinsonian potential.

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