NOVEL ANTI-INFLAMMATORY THERAPIES FOR PD

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。最近的一个大帕金森？帕金森病（PD）双胞胎研究表明，环境和毒性因素在引起典型PD中起主要作用（坦纳等人，JAMA，1999）。有趣的是，在尾壳核中观察到的神经炎症是病理生理学的一部分（布鲁克斯，1999）。在原发性PD中观察到的多巴胺（DA）末梢的进行性下降可以通过在9至14个月内低剂量暴露于线粒体毒素MPTP在食蟹猴中进行密切建模。我们通过DA末端的PET成像和MRS证明，这些灵长类动物提供了PD体征的退化和外观的生理图表（Brownell等人，Nat. Med.，1998年）。该数据特征使得能够设计用于现实地确定特发性PD中的毒性、神经炎症和神经保护的实验范例。在这个项目中，使用PD灵长类动物模型，我们现在建议研究抗炎药对多巴胺能系统的神经保护作用。基于几项研究，我们假设环氧合酶（考克斯）1和2抑制剂（吲哚美辛[1-（4-氯苯甲酰基）-5-甲氧基-2-甲基-1-H-吲哚-3-乙酸]）可以减少MPP+毒性引起的炎症反应，也可以减少慢性神经退行性过程。在非人灵长类动物中，重复MPTP治疗后黑质-纹状体多巴胺能系统出现缓慢进行性病变。使用外周苯二氮卓受体位点（11 C-PK 11195）的受体配体进行PET扫描，我们的初步实验表明，我们可以可视化CNS DA变性期间的神经炎症反应（由11 C-CFT确定）。这些测量将结合MRI和MRS研究乳酸和胆碱作为体内生物标志物的神经胶质炎症和毒性反应的黑质纹状体系统。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. A recent large Parkinson¿s disease (PD) twin study indicates that environmental and toxic factors play major roles in causing typical PD (Tanner et al. JAMA, 1999). Interestingly, neuroinflammation seen in the caudate-putamen is a part of the pathophysiology (Brooks, 1999). The progressive decline of dopamine (DA) terminals seen in idiopathic PD can be closely modeled in Macaca fascicularis by low-dose exposure to the mitochondrial toxin, MPTP, over nine to fourteen months. We demonstrated by PET imaging of DA terminal and MRS that such primates provide a physiological chart of degeneration and appearance of PD signs (Brownell et al., Nat. Med., 1998). This data profile enables the design of an experimental paradigm for realistically determining toxicity, neuroinflammation and neuroprotection in idiopathic PD. In this project using the PD primate model, we now propose to examine neuroprotection of the dopaminergic system by anti-inflammatory agents. Based on several studies, we hypothesize that a cyclooxygenase (COX) 1 and 2 inhibitor (indomethecin [1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1-H-indole-3-acetic acid]) can decrease inflammatory reactions caused by MPP+ toxicity and also reduce chronic neurodegenerative processes. In the non-human primate, a slow progressive lesion of the nigro-striatal dopaminergic system follows repeated MPTP treatment. Using PET scanning with a receptor ligand for the peripheral benzodiazepine receptor site (11C-PK11195), our preliminary experiments indicate that we can visualize the neuroinflammatory reactions during CNS DA degeneration (as determined by 11C-CFT). These measurements will be combined with MRI and MRS studies of lactate and choline as in vivo biomarkers for the glial inflammatory and toxic responses of the nigrostriatal system.