Activation of PPAR gamma receptors reduces levodopa-induced dyskinesias in 6-OHDA-lesioned rats

NEUROBIOLOGY OF DISEASE

卷:74

Article

Martinez, A. A.¹  Morgese, M. G.^1,3  Pisanu, A.²  Macheda, T.¹  Paquette, M. A.¹  Seillier, A.¹  Cassano, T.³  Carta, A. R.⁴  Giuffrida, A.¹ 

[1] Univ Texas San Antonio, Hlth Sci Ctr, Dept Pharmacol, San Antonio, TX 78229 USA

[2] CNR, Natl Res Council Italy, Inst Neurosci, Cagliari, Italy

[3] Univ Foggia, Dept Clin & Expt Med, I-71100 Foggia, Italy

[4] Univ Cagliari, Dept Biomed Sci, I-09124 Cagliari, Italy

关键词: Dyskinesia;    Parkinson's disease;    Cannabinoid;    PPAR gamma;    Levodopa;    Rosiglitazone;   

DOI  :  10.1016/j.nbd.2014.11.024

来源: Elsevier

【 摘 要 】

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 CB, 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 PPAR gamma 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 PPAR-gamma may represent a new pharmacological target for the treatment of LID. (C) 2014 Elsevier Inc. All rights reserved.

【 授权许可】

Free