title: Activation of PPAR gamma receptors reduces levodopa-induced dyskinesias in 6-OHDA-lesioned rats.
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.
authors.affiliation: Department of Pharmacology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA.
authors.forename: A A
authors.initials: AA
authors.lastname: Martinez
authors.affiliation: Department of Pharmacology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA; Department of Clinical and Experimental Medicine, University of Foggia, Viale Luigi Pinto 1, Foggia 71100, Italy.
authors.forename: M G
authors.initials: MG
authors.lastname: Morgese
authors.affiliation: Institute of Neuroscience, National Research Council of Italy (CNR), Cagliari, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Pisanu
authors.affiliation: Department of Pharmacology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA.
authors.forename: T
authors.initials: T
authors.lastname: Macheda
authors.affiliation: Department of Pharmacology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Paquette
authors.affiliation: Department of Pharmacology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA.
authors.forename: A
authors.initials: A
authors.lastname: Seillier
authors.affiliation: Department of Clinical and Experimental Medicine, University of Foggia, Viale Luigi Pinto 1, Foggia 71100, Italy.
authors.forename: T
authors.initials: T
authors.lastname: Cassano
authors.affiliation: Department of Biomedical Sciences, University of Cagliari, Italy.
authors.forename: A R
authors.initials: AR
authors.lastname: Carta
authors.affiliation: Department of Pharmacology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA. Electronic address: Giuffrida@uthscsa.edu.
authors.forename: A
authors.initials: A
authors.lastname: Giuffrida
mesh_terms: D000818:Animals; D018726:Anti-Dyskinesia Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004399:Dynorphins / Q000378:metabolism; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy* / Q000378:metabolism; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D007980:Levodopa / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity*; D008297:Male; D016627:Oxidopamine; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D020734:Parkinsonian Disorders / Q000188:drug therapy / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*
chemical_list: D018726:Anti-Dyskinesia Agents; D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D007980:Levodopa; D004399:Dynorphins; D016627:Oxidopamine; D048049:Extracellular Signal-Regulated MAP Kinases; D004298:Dopamine
keywords: Cannabinoid; Dyskinesia; Levodopa; PPARγ; Parkinson's disease; Rosiglitazone