NEUROPROTECTIVE PROPERTIES OF SELECTIVE PPAR GAMMA AGONIST LY554862

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 目的：探讨过氧化物酶体增殖物激活受体γ激动剂LY 554862对帕金森病的神经保护作用。 我们的实验室最近表明，长期口服吡格列酮诱导 在灵长类动物模型中对MPTP中毒的适度神经保护。基于这些信息，我们继续研究PPAR-γ活化作为PD的可能治疗靶点。 进度：过氧化物酶体增殖物激活受体（PPARs）是核受体超家族的一部分，是配体依赖性转录因子，具有三种亚型：<$，<$/<$和<$。 目前的证据表明，激活的过氧化物酶体增殖物激活受体-<$可以调节神经保护对帕金森病（PD）。 在MPTP小鼠PD模型中，已证明PPAR-γ激动剂如罗格列酮和吡格列酮可保护黑质纹状体免受损伤。 我们的实验室最近表明，在灵长类动物模型中，长期口服吡格列酮可诱导适度的神经保护作用，以对抗MPTP中毒。 基于这些信息，我们继续研究PPAR-γ活化作为PD的可能治疗靶点。 Eli Lilly Ltd.合成了一种新型的PPAR-γ激动剂LY 554862，由于其具有更高的脑渗透性，因此有可能比吡格列酮更有效。 因此，我们检查了口服LY 554862对MPTP处理的小鼠的影响。 在MPTP给药（30 mg/kg，腹膜内给药5天）之前3天，口服给药C57 BL/6和抗氧化反应元件（ARE）-hPAP报告小鼠LY 554862（30 mg/kg）或媒介物。 在最后一次MPTP注射后7天和最后一次LY 554862给药后处死ARE-hPAP报告小鼠，而在最后一次MPTP注射后21天和最后一次LY 554862给药后处死C57 BL/6小鼠。 初步结果显示，与安慰剂相比，用LY 554862处理的动物的纹状体中酪氨酸羟化酶（TH）的表达更高。 与安慰剂相比，在单独用30 mg/kg LY 554862（无MPTP）处理的动物中检测到更高水平的纹状体TH。 纹状体儿茶酚胺和ARE水平的分析尚未显示治疗组之间的差异。 目前，我们正在继续评估PPAR-γ激动剂LY 554862是否可以作为PD的候选治疗。 这项研究使用了WNPRC分析服务，是非人灵长类动物的先驱工作。 问题研究 正在编写一份出版物。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Objective: To assess neuroprotective properties of the PPAR GAMMA AGONIST LY554862 in treating Parkinson's disease. Our laboratory has recently shown that chronic oral administration of pioglitazone induces modest neuroprotection against MPTP intoxication in a primate model. Based on this information we continued to investigate PPAR-¿ activation as a possible therapeutic target for PD. Progress: Peroxisome proliferator-activated receptors (PPARs) are part of the nuclear receptor super family and are ligand-dependent transcription factors with three isoforms: ¿, ¿/¿ and ¿. Current evidence suggests that activation of PPAR-¿ can modulate neuroprotection against Parkinson's disease (PD). PPAR-¿ agonists such as rosiglitazone and pioglitazone have been shown to protect against nigrostriatal damage in MPTP mouse models of PD. Our laboratory has recently shown that chronic oral administration of pioglitazone induces modest neuroprotection against MPTP intoxication in a primate model. Based on this information we continued to investigate PPAR-¿ activation as a possible therapeutic target for PD. Eli Lilly Ltd. has synthesized a novel PPAR-¿ agonist, LY554862, which has the potential to be more effective than pioglitazone as it has higher brain penetration. We therefore examined the effects of oral administration of LY554862 to MPTP-treated mice. C57BL/6 and antioxidant response element (ARE)-hPAP reporter mice were orally administered LY554862 (30 mg/kg) or vehicle three days prior to MPTP administration (30 mg/kg, i.p for five days). ARE-hPAP reporter mice were sacrificed seven days after the last MPTP injection and following the last dose of LY554862, while C57BL/6 mice were sacrificed 21 days after the last MPTP injection and following the last dose of LY554862. Preliminary results showed higher expression of tyrosine hydroxylase (TH) in the striatum in animals treated with LY554862 compared to placebo. Higher levels of striatal TH were detected in animals treated with 30 mg/kg of LY554862 alone (no MPTP) compared to placebo. Analysis of striatal catecholamines and ARE levels have not revealed differences between treatment groups at this time. Currently, we are continuing to assess if the PPAR-¿ agonist, LY554862, can be a candidate therapy in PD. This research used WNPRC Assay Services and is precursor work to nonhuman primate studies. A publication is in preparation.