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，极大地影响患者的生活质量。它们经常被认为是帕金森病的症状，许多时候没有被诊断出来，总体上管理不善，因为它们对典型的抗帕金森病治疗没有反应。由于缺乏动物模型，在改进治疗和生物标记物方面的进展一直受到阻碍。我们通过静脉注射神经毒素6-OHDA建立了心脏自主神经紊乱的非人灵长类动物(NHP)模型，并开发了一系列测试来表征该模型。我们还证明了口服PPARγ激动剂吡格列酮可以调节炎症和氧化应激，诱导典型黑质纹状体变性的帕金森病模型的神经保护。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，其治疗效果是通过减少炎症和氧化应激来实现的。为了评估这一假说，我们提出：具体目标1：评估长期口服γ激动剂吡格列酮是否能防止6-羟基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功能障碍模型的炎症和氧化应激机制。我们将使用最先进的PET成像和放射配基在体内评估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指标(心电图、血压、活动度)、循环代谢物(例如：儿茶酚胺、细胞因子和PGCα-1)和形态数据(例如：局部心肌TH、HLADR、硝基酪氨酸和α突触核蛋白的表达)相关联，以分析不同指标与儿茶酚胺能丧失和保存的关系。这些技术将使我们能够评估神经退变和神经保护的机制，同时验证临床应用的生物标记物。

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 (PPARγ) 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 PPARγ 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.