Chapitre 4 : Discussion
4.10 Mécanismes opioïdergiques pouvant expliquer l'impact sur le comportement moteur
La figure 21 schématise les interactions entre les différents neurotransmetteurs et les peptides opioïdes au niveau synaptique ainsi que les réactions intracellulaires qui découlent de l'activation des récepteurs, culminant à la production du comportement moteur. L'augmentation du niveau de l'adénosine monophosphate cyclique (cAMP) induit l'activation des protéines kinases qui phosphorylent la « dopamine- and cAMP-regulated neuronal phosphoprotein » (DARPP-32) à la position de thréonine 34. Cela active cette dernière qui inhibe ensuite la protéine phosphatase 1 (PP1). PP1 contrôle entre autres l'activité des facteurs de transcription telles la « cAMP response element-binding protein » (CREB) et la famille des fos. Suite à l'activation de ces facteurs, il y a une modification des « immediate early genes » (IEG) et des « late-onset genes » (LOG) (Samadi et al., 2003, 2007). Ces mécanismes pourraient expliquer en partie de quelle manière la plasticité conséquente de la MP et de la DIL s'opère aux niveaux synaptique et de la transcription. Il faudrait voir comment la surexpression de pENK pourrait influencer ces mécanismes.
Figure 21. L'interaction entre les neurotransmetteurs et les peptides opioïdes striataux aux niveaux d'une synapse GABAergique striatopallidale (A) et striatonigrale (B) et la chaîne de modifications menant au comportement moteur.
Conclusion
Ce projet a permis d'obtenir plusieurs résultats afin de répondre à la question de départ. Selon nos observations, la surexpression de pENK aurait effectivement une influence positive sur la prévention ou encore la réduction de la DIL chez le modèle de souris unilatérale 6-OHDA de la maladie de Parkinson. Plusieurs éléments, que ce soit au niveau comportemental ou au niveau post-mortem, montrent que l'injection striatale de vecteur viral surexprimant le pENK ou seulement le GFP est associée à l'augmentation de l'ARNm de pENK au niveau du striatum antérieur chez le groupe pENK et au niveau du striatum postérieur chez le groupe GFP. De façon intéressante chez ces deux groupes (pENK, GFP), une réduction importante de la sévérité de la DIL (-70% à -82%) a été observée comparativement aux autres groupes contrôles ayant reçu l'injection striatale de salin ou sans injection striatale. Ces résultats soulèvent des questions importantes à répondre : comment et pourquoi le niveau d'ARNm de pENK est augmenté chez le groupe GFP ? Est- ce que les mécanismes impliqués dans la réduction de la dyskinésie sont identiques chez ces deux groupes ? En résumé, nos résultats montrent que l'augmentation striatale de l'ARNm de pENK peut retarder ou prévenir le développement de la DIL et réduire la sévérité de la dyskinésie.
Perspectives
En se penchant davantage sur nos résultats, nous avons observé qu'il y aurait en fait un effet de la surexpression de pENK encore plus grand lorsque la surexpression est globale et latérale comparativement à lorsqu'elle n'est que médiale. Bien que nous avions qu'un nombre limité de souris dans chaque sous-groupe formé afin de tirer cette conclusion, il n'en demeure que l'effet semble fort. Il serait intéressant d'étudier ce sujet davantage dans le futur afin de mieux comprendre le rôle des opioïdes dans différentes régions striatales sur la DIL. Un protocole pourrait être inclure des injections du vecteur viral seulement au niveau du striatum latéral et médial afin de bien faire la part de l'apport de chaque région dans le contrôle de la DIL. Également, un autre élément à tester dans le futur afin de rajouter aux résultats que nous avons obtenus serait de sous-exprimer pENK. Il serait fort intéressant de
vérifier si dans ce cas, il y aurait une augmentation du niveau de la dyskinésie. En plus des neuropeptides, tout ce qui entoure les récepteurs est un aspect fort intriguant concernant la grande question du rôle des opioïdes dans la DIL, car bien qu'une sur- ou sous-expression puisse être induite, l'activité en découlant passera par les récepteurs. Il serait pertinent de faire des expériences à ce niveau également. Ce projet est une première étape de plusieurs en perspective visant à mieux comprendre le rôle des neuropeptides opioïdes dans la maladie de Parkinson et à trouver de nouvelles pistes de traitements afin d'améliorer la qualité de vie des patients.
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