Validation of PPARgamma agonists as anti-dyskinetic drugs

University Of Texas Hlth Science Center, San Antonio TX

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Abstract

DESCRIPTION (provided by applicant): Levodopa (L-DOPA) remains the gold standard therapy for Parkinson's disease (PD) treatment, but it's long- term use is associated with disabling side effects consisting of uncontrolled involuntary movements known as L-DOPA-induced dyskinesias (LID). Being PD the second most frequent neurodegenerative disorder and L- DOPA the most effective treatment, there is a strong need to discover new pharmacological targets and pharmacotherapies to prevent the development of LID while maintaining L-DOPA beneficial effects. Rats with unilateral 6-hydroxydopamine (6-OHDA) lesion of the nigrostriatal pathway and chronically treated with L- DOPA represent a cost-efficient and pharmacologically validated model to test new anti-dyskinetic drugs. In these animals, previous studies have shown a significant upregulation of striatal molecular markers of dyskinesia, such as prodynorphin, zif268 and delta FosB, which are under the control of the transcription factor Activator Protein-1 (AP-1). Preliminary work carried out in our laboratory on dyskinetic 6-OHDA rats indicated that activation of peroxisome proliferator activated receptor gamma (PPAR3), a member of the super family of nuclear receptors, ameliorates LID once they are fully established. This proposal will test the hypothesis that pharmacological activation of PPAR3 prevents the development of dyskinesias and decreases the expression of dyskinesia markers and AP-1 function. The first specific aim will employ behavioral tests (Abnormal Involuntary Movement scoring and different sensory-motor tests) to investigate whether co-administration of L- DOPA+PPAR3 agonist (rosiglitazone) prevent the appearance of LID without affecting L-DOPA anti- parkinsonian activity. Selective PPAR3 antagonists, as well as siRNA-mediated knockdown of striatal PPAR3 will be used to validate PPAR3 as an anti-dyskinetic target. Given the ability of activated PPAR3 to alter gene transcription, the second specific aim will investigate whether PPAR3 activation affects the expression of the molecular markers of LID and/or AP-1 function by direct interaction of PPAR3 with AP-1 binding protiens and/or by altering AP-1 ability to initiate gene transcription. As the PPAR3 agonist rosiglitazone is FDA-approved for the treatment of diabetes, this study will provide important translational data for the repurposing of this drug for the treatment of LID. PUBLIC HEALTH RELEVANCE: Despite L-DOPA initial beneficial effects in treating Parkinson's disease, its prolonged use results in the development of abnormal involuntary movements known as dyskinesia. Recent evidence suggests that activation of the nuclear receptor, PPARgamma, ameliorates these unwanted side effects once they are fully established. This proposal investigates whether co-administration of L-DOPA and a PPARgamma agonist (rosiglitazone) prevents the development of dyskinesias in a rodent model of Parkinson's disease. )