Activation of PPAR-gamma in a Monkey Model of Cardiac Dysautonomia

描述（申请人提供）：帕金森病（PD）的非运动症状，如心脏自主神经功能障碍（dysautonomia），极大地影响患者的生活质量。它们经常被认为是PD症状，很多时候未被诊断，总体上管理不善，因为它们对典型的抗帕金森治疗没有反应。由于缺乏动物模型，改善治疗方法和生物标志物的进展受到阻碍。我们通过静脉注射神经毒素6-OHDA建立了一种非人类灵长类动物（NHP）心脏自主神经障碍模型，并开发了一系列测试来表征该模型。我们还证明口服过氧化物酶体增殖物激活受体γ (PPAR)激动剂吡格列酮可调节炎症和氧化应激，在典型黑质纹状体变性的NHP PD模型中诱导神经保护。基于这些研究，我们假设吡格列酮可以在NHP心脏自主神经障碍模型中起到神经保护作用，并且治疗效果是通过减少炎症和氧化应激介导的。为了评估这一假设，我们提出：具体目标1：评估慢性口服PPAR是否有效？激动剂吡格列酮可预防6-羟多巴胺诱导的外周儿茶酚胺能神经变性，并下调心脏自主神经异常NHP模型中的炎症和氧化应激机制。我们将使用最先进的PET成像和放射配体来评估治疗前后儿茶酚胺能神经支配（[C11]MHED）、炎症（[C11]PK11195）和氧化应激（[61/64Cu]ATSM）的体内心脏标志物。我们将把成像数据与临床测量（心电图、血压、活动）、循环代谢物（如儿茶酚胺、细胞因子和PGCα-1）和形态学数据（如TH、HLA-DR、硝基酪氨酸和α突触核蛋白表达的区域心肌定量）联系起来，分析不同测量与儿茶酚胺能损失和保存的关系。这些技术将使我们能够评估神经变性和神经保护的机制，同时验证临床应用的生物标志物。

DESCRIPTION (provided by applicant): 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 PGCα-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.