NOVEL ANTI-INFLAMMATORY THERAPIES FOR PD

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。最近的一项大型帕金森病（PD）双胞胎研究表明，环境和毒性因素在导致典型PD中起主要作用（Tanner等）。《美国医学会杂志》,1999)。有趣的是，在尾状壳核中发现的神经炎症是病理生理学的一部分（Brooks, 1999）。在特发性PD中观察到的多巴胺（DA）终末的进行性下降可以通过低剂量暴露于线粒体毒素（MPTP）超过9至14个月的Macaca fascularis密切模拟。我们通过对DA终端和MRS的PET成像证明，这些灵长类动物提供了变性和PD症状出现的生理图表（Brownell et al., Nat. Med., 1998）。该数据配置文件能够设计一个实验范例，以实际确定特发性PD的毒性，神经炎症和神经保护。在这个项目中，使用PD灵长类动物模型，我们现在建议检查抗炎剂对多巴胺能系统的神经保护作用。基于几项研究，我们假设环加氧酶（COX） 1和2抑制剂（吲哚美辛[1-（4-氯苯甲酰）-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，并减少慢性神经退行性过程。在非人类灵长类动物中，重复MPTP治疗后，黑纹状体多巴胺能系统出现缓慢进行性病变。通过PET扫描外周苯二氮卓受体位点（11C-PK11195）的受体配体，我们的初步实验表明，我们可以可视化中枢神经系统DA变性期间的神经炎症反应（由11C-CFT确定）。这些测量将与乳酸和胆碱的MRI和MRS研究相结合，作为黑质纹状体系统神经胶质炎症和毒性反应的体内生物标志物。

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.