Évaluation de nouvelles prodrogues dans l’ablation chimiogénétique des neurones dopaminergiques par nitroreductase pour modéliser la maladie de Parkinson
DOI :
https://doi.org/10.18192/osurj.v5i2.8050Résumé
La maladie de Parkinson est une maladie neurodégénérative progressive, principalement caractérisée par la perte de neurones dopaminergiques dans le mésencéphale. Cette perte entraîne des symptômes moteurs comme les tremblements, la rigidité musculaire et la lenteur des mouvements, aussi appelée bradykinésie, ainsi que plusieurs symptômes non moteurs. La maladie touche plus de six millions de personnes dans le monde, mais les traitements actuels servent surtout à soulager les symptômes. Ils ne permettent pas encore d’arrêter la progression de la maladie.
Pour cette raison, il est important de développer des modèles fiables et faciles à reproduire afin d’étudier la perte des neurones dopaminergiques et de tester de nouvelles approches thérapeutiques. Le poisson-zèbre, ou Danio rerio, est un modèle très utile dans ce contexte, car il présente plusieurs similarités neurofonctionnelles et comportementales avec l’humain. Il est aussi largement utilisé dans les études sur les maladies neurodégénératives, le développement du système nerveux et les effets des médicaments sur le cerveau.
Dans cette étude, l’ablation chimiogénétique a été utilisée comme approche pour éliminer de façon contrôlée les neurones dopaminergiques. Cette méthode est intéressante, car elle permet de cibler précisément certains neurones, au moment voulu, tout en limitant la toxicité générale. Elle permet donc de mieux modéliser la neurodégénérescence et d’étudier la régénération neuronale, ce qui est plus difficile avec des approches uniquement chimiques ou génétiques.
L’étude repose sur un système d’ablation chimiogénétique utilisant la nitroreductase bactérienne, ou NTR, exprimée dans les neurones dopaminergiques de larves de poisson-zèbre. Plus précisément, la lignée Tg(dat:CFP-NTR) a été utilisée. Dans ce modèle, la NTR transforme des prodrogues normalement peu toxiques, comme le métronidazole et le ronidazole, en composés toxiques capables de provoquer la mort des cellules ciblées. Cela permet une ablation des neurones dopaminergiques contrôlée dans l’espace et dans le temps.
La survie des neurones dopaminergiques a été mesurée dans différentes régions du cerveau, notamment le bulbe olfactif, le télencéphale et le diencéphale. Pour cela, deux marqueurs ont été utilisés : la tyrosine hydroxylase, un marqueur des neurones dopaminergiques, et la protéine fluorescente cyan, exprimée sous le contrôle d’éléments régulateurs du gène du transporteur de la dopamine. Des tests comportementaux ont aussi été réalisés afin d’évaluer la locomotion des larves un et deux jours après le traitement.
Les résultats n’ont pas montré de diminution significative du nombre de neurones dopaminergiques ni de déficit comportemental par rapport aux groupes témoins. Ce résultat pourrait s’expliquer par plusieurs limites, notamment la faible solubilité et la faible biodisponibilité des prodrogues utilisées, l’efficacité catalytique limitée de la première génération de NTR par rapport à NTR 2.0, ainsi que la possibilité d’une régénération neuronale rapide chez les larves de poisson-zèbre.
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