Identification of antiparkinsonian drugs in the 6-hydroxydopamine zebrafish model

Rita L. Vaz, Sara Sousa, Diana Chapela, Herma C. van der Linde, Rob Willemsen, Ana D. Correia, Tiago F. Outeiro, Nuno D. Afonso

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Article number172828
JournalPharmacology Biochemistry and Behavior
Volume189
DOIs
Publication statusPublished - 1 Feb 2020

Fingerprint

Antiparkinson Agents
Oxidopamine
Zebrafish
Parkinson Disease
Pharmaceutical Preparations
Isradipine
Larva
Screening
nabumetone
Molecules
Neurons
Secondary Parkinson Disease
Stavudine
Amantadine
Confocal microscopy
Movement Disorders
Parkinsonian Disorders
Levodopa
Confocal Microscopy
Vertebrates

Keywords

  • Drug screening
  • Parkinson's disease
  • Repositioning
  • Zebrafish

Cite this

Vaz, R. L., Sousa, S., Chapela, D., van der Linde, H. C., Willemsen, R., Correia, A. D., ... Afonso, N. D. (2020). Identification of antiparkinsonian drugs in the 6-hydroxydopamine zebrafish model. Pharmacology Biochemistry and Behavior, 189, [172828]. https://doi.org/10.1016/j.pbb.2019.172828
Vaz, Rita L. ; Sousa, Sara ; Chapela, Diana ; van der Linde, Herma C. ; Willemsen, Rob ; Correia, Ana D. ; Outeiro, Tiago F. ; Afonso, Nuno D. / Identification of antiparkinsonian drugs in the 6-hydroxydopamine zebrafish model. In: Pharmacology Biochemistry and Behavior. 2020 ; Vol. 189.
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Vaz, RL, Sousa, S, Chapela, D, van der Linde, HC, Willemsen, R, Correia, AD, Outeiro, TF & Afonso, ND 2020, 'Identification of antiparkinsonian drugs in the 6-hydroxydopamine zebrafish model', Pharmacology Biochemistry and Behavior, vol. 189, 172828. https://doi.org/10.1016/j.pbb.2019.172828

Identification of antiparkinsonian drugs in the 6-hydroxydopamine zebrafish model. / Vaz, Rita L.; Sousa, Sara; Chapela, Diana; van der Linde, Herma C.; Willemsen, Rob; Correia, Ana D.; Outeiro, Tiago F.; Afonso, Nuno D.

In: Pharmacology Biochemistry and Behavior, Vol. 189, 172828, 01.02.2020.

Research output: Contribution to journalArticle

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T1 - Identification of antiparkinsonian drugs in the 6-hydroxydopamine zebrafish model

AU - Vaz, Rita L.

AU - Sousa, Sara

AU - Chapela, Diana

AU - van der Linde, Herma C.

AU - Willemsen, Rob

AU - Correia, Ana D.

AU - Outeiro, Tiago F.

AU - Afonso, Nuno D.

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