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P-O Fernagut, E. Bezard et al. dans Biological Psychiatry

L’inactivation des neurones striataux exprimant FosB/ΔFosB réduit les dyskinésies L-Dopa-induites tout en potentialisant l’effet antiparkinsonien.

Le 9 septembre 2014

Selective Inactivation of Striatal FosB/ΔFosB-Expressing Neurons Alleviates L-Dopa-Induced Dyskinesia.
Engeln M, Bastide MF, Toulmé E, Dehay B, Bourdenx M, Doudnikoff E, Li Q, Gross CE, Boué-Grabot E, Pisani A, Bezard E, Fernagut PO. Biol Psychiatry. 2014 Jul 15. pii: S0006-3223(14)00506-X. doi: 10.1016/j.biopsych.2014.07.007. [Epub ahead of print]




Le traitement de la maladie de Parkinson par la L-Dopa entraine des effets secondaires caractérisés par des mouvements involontaires (dyskinésies).
Ces dyskinésies induites par la L-Dopa sont associées à une accumulation des facteurs de transcription FosB et ΔFosB. Dans cette étude, nous montrons que l’inactivation sélective des neurones exprimant FosB/ΔFosB permet non seulement de réduire les dyskinésies mais également d’augmenter l’effet thérapeutique de la L-Dopa.


Inactivating striatal FosB/ΔFosB expressing neurons reduces L-Dopa-induced dyskinesia while potentiating the antiparkinsonian effect.

L-Dopa-induced dyskinesia (LID) are debilitating abnormal involuntary movements occurring during symptomatic treatment of Parkinson’s disease and there is currently no satisfying solution for their clinical management since all therapeutic strategies aiming at reducing the severity of dyskinesia bear also the potential for interfering with the antiparkinsonian action of L-Dopa. Dyskinesias are associated with a number of molecular alterations in the basal ganglia including an overexpression of the transcription factors FosB and ΔFosB in the striatum. However, the relationship between the electrical activity of FosB/ΔFosB-expressing neurons and LID manifestation is unknown. Here we used the Daun02 prodrug-inactivation method to directly investigate a causal link between the activity of FosB/ΔFosB-expressing neurons and LID. When Daun02 is converted into daunorubicin by beta-galactosidase, daunorubicin reduces Ca2+-dependent action potentials and therefore inhibits neuronal activity. Lentiviral expression of ß-galactosidase under the control of the FosB promoter thus enables a selective inactivation of FosB/ΔFosB-expressing neurons In this study, we demonstrate that daunorubicin and conversion of daun02 into daunorubicin by beta-galactosidase decrease the excitability of striatal neurons in vitro as well as in rat brain slices. Using a cell-specific expression of beta-galactosidase in FosB/ΔFosB-expressing neurons, we show that the inactivation of these neurons with Daun02 decreases the severity of abnormal involuntary movements in both rat and monkey models of L-Dopa-induced dyskinesia. In addition, the reduction of dyskinesia following inactivation of FosB/ΔFosB-expressing neurons was paralleled by an enhanced antiparkinsonian effect of L-Dopa in both models. Our findings provide direct evidence that the electrophysiological activity of striatal neurons expressing FosB/ΔFosB underlies abnormal involuntary movements triggered by L-Dopa. Our data also show that the activity of these neurons blunts the symptomatic effect of the antiparkinsonian treatment. By revealing the dual role of these FosB/ΔFosB neurons, our study indicate that a combination of positive effects upon dyskinesia and parkinsonism could be achieved if the strategy is specific enough of the FosB/ΔFosB-accumulating striatal neurons.

 

Olivier Fernagut est chargé de recherche au CNRS à l'Institut des Maladies Neurodégénératives dans l'équipe : Physiopathologie des syndromes parkinsoniens.

Erwan Bezard  est directeur de ll'Institut des Maladies Neurodégénératives 

 

Pierre-Olivier Fernagut (pierre-olivier.fernagut @ u-bordeaux.fr)
Dernière mise à jour le 12.09.2014

1ers Auteurs


Michel Engeln est actuellement postdoc à l'Université du Maryland 


Matthieu Bastide, doctorant à l'IMN soutiendra sa thèse le 18 Sept 2014