Title:  Activation of PPAR gamma receptors reduces levodopa-induced dyskinesias in 6-OHDA-lesioned rats
Issue Date:  2015
Internal authors: 
Authors:  Martinez, AA; Morgese, MG; Pisanu, A; Macheda, T; Paquette, MA; Seillier, A; Cassano, T; Carta, A; Giuffrida, A
Number of authors:  9
Language:  Inglese
International coauthors: 
Volume:  74
First page:  295
Last page:  304
Number of pages:  10
Digital Object Identifier (DOI):  10.1016/j.nbd.2014.11.024
Pubmed identifier:  25486547
Scopus identifier:  2-s2.0-84919359735
ISI identifier:  WOS:000349655900027
Abstract:  Long-term administration of l-3,4-dihydroxyphenylalanine (levodopa), the mainstay treatment for Parkinson's disease (PD), is accompanied by fluctuations in its duration of action and motor complications (dyskinesia) that dramatically affect the quality of life of patients. Levodopa-induced dyskinesias (LID) can be modeled in rats with unilateral 6-OHDA lesions via chronic administration of levodopa, which causes increasingly severe axial, limb, and orofacial abnormal involuntary movements (AIMs) over time. In previous studies, we showed that the direct activation of CB1 cannabinoid receptors alleviated rat AIMs. Interestingly, elevation of the endocannabinoid anandamide by URB597 (URB), an inhibitor of endocannabinoid catabolism, produced an anti-dyskinetic response that was only partially mediated via CB1 receptors and required the concomitant blockade of transient receptor potential vanilloid type-1 (TRPV1) channels by capsazepine (CPZ) (Morgese et al., 2007). In this study, we showed that the stimulation of peroxisome proliferator-activated receptors (PPAR), a family of transcription factors activated by anandamide, contributes to the anti-dyskinetic effects of URB+CPZ, and that the direct activation of the PPARγ subtype by rosiglitazone (RGZ) alleviates levodopa-induced AIMs in 6-OHDA rats. AIM reduction was associated with an attenuation of levodopa-induced increase of dynorphin, zif-268, and of ERK phosphorylation in the denervated striatum. RGZ treatment did not decrease striatal levodopa and dopamine bioavailability, nor did it affect levodopa anti-parkinsonian activity. Collectively, these data indicate that PPARγ may represent a new pharmacological target for the treatment of LID.
Keywords:  Cannabinoid; Dyskinesia; Levodopa; PPARγ; Parkinson's disease; Rosiglitazone
Type: 1.1 Articolo in rivista

Files in This Item:
File Description Type License  
Martinez et al_2015.pdf  Editoriale Administrator    Request a copy

Questionnaire and social

Share on: