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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Pharmacol. | doi: 10.3389/fphar.2019.01233

Knock-down of GPR88 in the dorsal striatum alters the response of medium spiny neurons to the loss of DA input and L-DOPA.

 Manuela Ingallinesi1,  Benjamin Galet1, Jonathan Pegon1, Nicole Faucon Biguet1, Anh Do Thi1, Mark J. Millan2,  Clotilde Mannoury La Cour2 and  Rolando Meloni1*
  • 1Dept of Biotechnology and Biotherapy, INSERM U1127 Institut du Cerveau et de la Moelle épinière (ICM), France
  • 2Servier (France), France

The effects of L-3,4-Dihydroxyphenilanlanine (L-DOPA) treatment for replacing the dopamine (DA) loss in Parkinson’s disease (PD) progressively wear off and are hindered by the development of dyskinesia, prompting the search of new treatments. The orphan GPCR Gpr88 represents a potential new target, as it is highly and almost exclusively expressed in the projecting GABAergic medium spiny neurons of the striatum, is implicated in motor activity and is downregulated by 6-OHDA lesions, an effect that is reversed by L-DOPA.
Thus, to evaluate Gpr88 as a potential target for the management of Parkinson’s disease and L-DOPA-induced dyskinesia (LID), we inactivated Gpr88 by lentiviral-mediated knock-down with a specifically designed microRNA (miR) (KD-Gpr88) in a 6-OHDA rat model of hemi-parkinsonism. Then, we investigated the effects of the KD-Gpr88 in the DA-deprived dorsal striatum on circling behavior and LID as well as on specific markers of striatal neuron activity.
The KD-Gpr88 reduced the acute amphetamine-induced and increased L-DOPA-induced turning behavior. Moreover, it normalized the upregulated expression of striatal Gad67 and Proenkephalin provoked by the 6-OHDA lesion. Finally, despite promoting FosB accumulation, the KD-Gpr88 was associated neither with the upregulation of Prodynorphin, which is causally linked to the severity of LID, nor with the aggravation of LID following chronic L-DOPA treatment in 6-OHDA-lesioned rats.
These results thus justify further evaluation of Gpr88 as a potentially novel target for the management of PD as an alternative to L-DOPA therapy.

Keywords: GPR88, 6-OHDA animal model of Parkinson's disease, Turning behavior, lentiviral vector constructs, L-DOPA-induced dyskinesia, miR-mediated knock-down

Received: 22 May 2019; Accepted: 27 Sep 2019.

Copyright: © 2019 Ingallinesi, Galet, Pegon, Faucon Biguet, Do Thi, Millan, Mannoury La Cour and Meloni. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Rolando Meloni, INSERM U1127 Institut du Cerveau et de la Moelle épinière (ICM), Dept of Biotechnology and Biotherapy, Paris, 75013, Île-de-France, France, rolando.meloni@upmc.fr