Targeting peroxisome proliferator-activated receptors (ppar) for the treatment l-dopa-induced dyskinesias

Abstract

L administration of L-DOPA to Parkinson’s disease (PD) patients is accompanied by fluctuations in its duration of action and chorea-like motor complications known as L-DOPA-induced dyskinesias (LID). As L-DOPA is the most effective treatment for PD, there is a strong need to identify new pharmacological targets to control LID while maintaining L-DOPA beneficial effects.LID can be modeled in rats with unilateral 6-OHDA lesions via chronic administration of L-DOPA, which induces increasingly severe axial, limb and oro-facial abnormal involuntary movements (AIMs). Previous studies in our laboratory showed that systemic administration of the PPAR gamma agonist rosiglitazone (5 & 10 mg/kg, i.p.) ameliorated axial, oral and limb AIMs without reducing L-DOPA’s anti-parkinsonian activity. Rosiglitazone also attenuated the L-DOPA-induced elevation of dyskinesia (Zif-268 and prodynorphin) and inflammation (COX-2) markers within the denervated striatum. Interestingly, chronic L-DOPA significantly increased the PPAR beta/delta isoform in dyskinetic rats and this elevation was reversed by rosiglitazone treatment. These data suggest that targeting PPAR gamma/delta receptors can ameliorate dyskinetic symptoms, possibly by reducing the underlying neuroinflammatory response observed in PD. Supported by RO1 -NS050401-06 (A.G).