Testing of Novel Prodrugs in Nitroreductase Chemogenetic Ablation of Dopaminergic Neurons for Parkinson’s Disease Modelling / Évaluation de nouvelles prodrogues dans l’ablation chimiogénétique des neurones dopaminergiques par nitroreductase pour modéliser la maladie de Parkinson
Testing of Novel Prodrugs in Nitroreductase Chemogenetic Ablation of Dopaminergic Neurons for Parkinson’s Disease Modelling / Évaluation de nouvelles prodrogues dans l’ablation chimiogénétique des neurones dopaminergiques par nitroreductase pour modéliser la maladie de Parkinson
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Original abstract
Parkinson’s disease is a progressive neurodegenerative disorder highlighted by the loss of midbrain dopaminergic neurons, resulting in tremors, stiffness, slowness of movement (bradykinesia) as well as non-motor symptoms. Affecting over six million people globally, current treatments are largely symptomatic and do not halt disease progression. Developing a reliable, scalable model of dopaminergic neuron ablation is therefore critical for therapeutic discovery. With its close neurofunctional and behavioural similarities to humans, the zebrafish (Danio rerio) is an excellent model for neurodegenerative, neurodevelopmental, and neuropharmacological studies. Chemogenetic ablation is preferred because it enables highly specific, temporally controlled, and minimally toxic ablation of dopaminergic neurons, allowing accurate modelling of neurodegeneration and facilitating studies of neuronal regeneration, which are not possible with purely chemical or genetic approaches. This study utilizes a chemogenetic ablation method based on the bacterial nitroreductase (NTR) expressed in dopaminergic neurons of zebrafish larvae, specifically the Tg(dat:CFP-NTR) zebrafish line. This allows for dopaminergic neuron ablation assessment across different brain regions. In this system, NTR converts otherwise non-toxic prodrugs, metronidazole and ronidazole into cytotoxic compounds, enabling spatial and temporally controlled ablation. Dopaminergic neuron survival was quantified in the olfactory bulb, telencephalon, and diencephalon using tyrosine hydroxylase and cyan fluorescent protein , the latter expressed under regulatory elements of the dopamine transporter gene. Behavioural assays assessed locomotor function at one and two days post-treatment. No significant decreases in dopaminergic neuron counts or behavioural deficits were detected relative to vehicle controls. This outcome likely arose from several limitations, including poor prodrug solubility and bioavailability, the limited catalytic efficiency of first-generation NTR relative to NTR 2.0, and potential rapid neuronal regeneration in larval organisms.