Nonmotor symptoms of Parkinson's disease (PD), such as cardiac autonomic dysfunction (dysautonomia), greatly affect patients'quality of life. They are frequently unrecognized as PD symptoms, many times undiagnosed and overall poorly managed, as they do not respond to typical anti-parkinsonian therapies. Progress towards improving treatments and biomarkers have been hampered by the lack of animal models. We have developed a nonhuman primate (NHP) model of cardiac dysautonomia by intravenous delivery of the neurotoxin 6-OHDA and developed a battery of tests to characterize the model. We have also demonstrated that oral dosing of the peroxisome proliferator activator receptor gamma (PPAR?) agonist pioglitazone modulates inflammation and oxidative stress, inducing neuroprotection in a NHP model of PD with typical nigrostriatal degeneration. Based on these studies we hypothesize that pioglitazone can be neuroprotective in the NHP model of cardiac dysautonomia and that the therapeutic effects are mediated via a reduction in inflammation and oxidative stress. To evaluate this hypothesis we propose:
Specific Aim 1 : To evaluate whether chronic oral dosing of the PPAR? agonist pioglitazone prevents 6-OHDA-induced peripheral catecholaminergic neurodegeneration and downregulates mechanisms of inflammation and oxidative stress in a NHP model of cardiac dysautonomia. We will use state-of-the-art PET imaging and radioligands to evaluate in vivo cardiac markers of catecholaminergic innervation ([C11]MHED), inflammation ([C11]PK11195) and oxidative stress ([61/64Cu]ATSM) before and after treatments. We will correlate the imaging data with clinical measures (ECG, blood pressure, activity), circulating metabolites (e.g.: catecholamines, cytokines and PGC?-1) and morphological data (e.g.: regional myocardial quantification of TH, HLA-DR, nitrotyrosine and alpha synuclein expression), to analyze how the different measures relate to catecholaminergic loss and preservation. These technologies will allow us to evaluate mechanisms of neurodegeneration and neuroprotection while validating biomarkers for clinical application.

Public Health Relevance

This proposal aims to evaluate whether pioglitazone, an antidiabetic drug with neuroprotective properties, can prevent neurodegeneration in the heart in a monkey model of cardiac dysautonomia. It has the potential to help patients by providing for the first time with a neuroprotective therapy for autonomic dysfunction, while developing minimally invasive methods for evaluation and understanding of the mechanisms of cardiac denervation and treatment efficacy.

Agency
National Institute of Health (NIH)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS084158-01A1
Application #
8698569
Study Section
Clinical Neuroscience and Neurodegeneration Study Section (CNN)
Program Officer
Sieber, Beth-Anne
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Physics
Type
Schools of Medicine
DUNS #
City
Madison
State
WI
Country
United States
Zip Code
53715
Joers, Valerie; Dilley, Kristine; Rahman, Shahrose et al. (2014) Cardiac sympathetic denervation in 6-OHDA-treated nonhuman primates. PLoS One 9:e104850