Objective/Rationale:
We plan to develop new pharmacological approaches to treat levodopa-induced dyskinesia (LID) in a pre-clinical model of Parkinson’s disease (PD). Preliminary data from our laboratory suggest that administration of rosiglitazone, an activator of peroxisome proliferator-activated receptor gamma (PPARgamma), ameliorates abnormal involuntary movements in parkinsonian models receiving chronic levodopa. The proposed studies will test drugs that target PPARgamma to determine whether these compounds decrease LID without preventing the beneficial effects of levodopa.
Project Description:
We will:
- investigate whether rosiglitazone (ROSI) decreases LID without preventing the beneficial anti-parkinsonian effects of levodopa, and we will verify that this effect depends on activation of brain PPARgamma via pharmacological blockade of these receptors. We will study also whether ROSI enters the brain and decreases striatal levels of levodopa and dopamine.
- determine the anatomical localization of PPARgamma in the basal ganglia circuitry known to be involved in PD (direct and indirect pathways). We will also determine whether ROSI alters the expression of dyskinesia markers in the brain.
- assess whether PPARb/d, a receptor subtype that is up-regulated by PPARgamma, is involved in ROSI’s anti-dyskinetic effect. Specifically, we will test whether ROSI affects PPARb/d expression in the brain and whether the selective pharmacological blockade of PPARb/d prevents the anti-dyskinetic effects of ROSI.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Although levodopa alleviates PD symptoms in the early stages of the disease, its chronic use causes side effects known as LID in the vast majority of patients. Current treatments for LID are not effective, and there is a strong need to develop alternative pharmacotherapies. This study will validate a new pharmacological target for LID treatment using an FDA-approved drug (ROSI).
Anticipated Outcome:
We expect ROSI to significantly reduce LID and its associated molecular markers without affecting levodopa’s anti-parkinsonian activity. This point is particularly exciting as this PPARgamma activator is FDA-approved for the treatment of insulin resistance and has potential antidepressant and cognitive-enhancing effects, but no abuse liability. Thus, the possibility to extend the use of this drug to the treatment of PD makes it very attractive for relatively quick translation into clinical trials.
Progress Report
Our data indicate that systemic administration of the PPARgamma activator Rosiglitazone significantly ameliorates levodopa-induced oral, axial and limb dyskinesias in 6-OHDA-treated pre-clinical models of Parkinson’s disease. This effect was dose-dependent and mediated via stimulation of PPARgamma receptors only in the case of axial and limb dyskinesias. Application of a selective PPARgamma blocker was not able to reverse the beneficial effects of Rosiglitazone on oro-facial dyskinesias, suggesting a different mechanism of action.
We also found that Rosiglitazone administration did not change levodopa and dopamine availability in the brain, nor did it affect the antiparkinsonian activity of levodopa, suggesting that the antidyskinetic effects of Rosiglitazone are not related to modifications of levodopa or dopamine levels in the striatum.
In a second battery of experiments, we assessed the anatomical distribution of PPARgamma receptors in the brain. PPAR-gamma receptors were constitutively expressed in enkephalin-positive (putative D2-receptor-containing neurons), as well as in enkephalin-negative (putative D1-containing neurons) of either the intact or the dopamine-depleted hemisphere. The dopamine-depleted striatum displayed similar receptor levels upon levodopa treatment as compared to the intact side. However, Rosiglitazone co-administration reduced PPAR-gamma levels in the denervated side.
Final Outcome
In this study we showed that the PPAR-gamma receptor, a transcription factor traditionally implicated in the regulation of lipid metabolism, energy homeostasis and neuroinflammation, represents a new pharmacological target for the treatment of L-DOPA-induced dyskinesias (LID) in Parkinson’s disease (PD). Using the 6-OHDA pre-clinical model of PD, we found that PPAR-gamma receptors are localized in brain areas that are critical for LID development, and that their activation by the drug Rosiglitazone produces a reduction of L-DOPA-induced abnormal involuntary movements and their associated bio-markers. Rosiglitazone did not alter the antiparkinsonian effect of L-DOPA, suggesting that it can be administered in combination with L-DOPA to control and ameliorate motor abnormalities resulting from long-term L-DOPA treatment.
Presentations & Publications
Report (and include copies of) any presentations, abstracts, findings, or papers (submitted for publication, in press, or published) that resulted from the work made possible by this award.
1) Martinez AA, Pisanu A, Carta A, Giuffrida A. Activation of PPARgamma receptors reduces levodopa-induced dyskinesias without affectiong dopamine bioavailability in 6-OHDA-treated [pre-clinical models]. Oral Presentation, Society for Neuroscience Annual Meeting, Washington DC (2011)
November 2012