The Role of PPAR Agonists in Inflammation and stroke

PPAR 激动剂在炎症和中风中的作用

• 批准号: 6979790
• 负责人: SOPHIA SUNDARARAJAN
• 金额: $ 16.78万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-12-15 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6979790
• 关键词: Role; PPAR; Agonists; Inflammation; stroke

DESCRIPTION (provided by applicant): Stroke is a devastating disease. We desperately need to understand mechanisms of injury and recovery following ischemic stroke in order to design treatments that will limit ischemic injury and promote recovery. Inflammation exacerbates ischemic injury and may play a role in remodeling and recovery following stroke. Our long term objective is to clarify the role of inflammation in cerebral ischemia both in the acute and chronic time frames. To accomplish this, we propose to use a new class of drugs, PPARgamma agonists, which have anti-inflammatory properties. Troglitazone, a PPARgamma agonist, reduces the expression of the pro-inflammatory cytokines and other inflammatory molecules. Preliminary data show that troglitazone reduces infarct size following focal ischemia in rats and that immunoreactivity against pro-inflammatory cytokines is reduced in the same animals. Furthermore, we show that PPARgamma expression is increased following cerebral ischemia. This increase is present within hours and persists for least one week. Experiments are designed to test the role of PPARgamma activation in neuroprotection using additional PPARgamma agonists and antagonists. The time period in which the activation must occur will be examined. We propose to use a combination of Western blotting, quantitative rt-PCR and immunocytochemistry to assay the contribution of inflammation to the observed neuroprotection. We will specifically examine the role played by pro-inflammatory cytokines by administering compounds that block the cytokines, interleukin-l beta and tumor necrosis factor alpha along with troglitazone to animals undergoing middle cerebral artery occlusion. We propose to further examine the expression of PPARgamma in ischemic brain and explore the effects of PPARgamma agonists on this expression. Finally the ability of PPARgamma agonists to modulate functional outcome after the time when infarct volume has been determined is explored. Preliminary data that suggests that troglitazone may improve outcome when administered twenty-four hours and four days after focal stroke. When administered at this time, troglitazone does not reduce infarct size. These preliminary data will be confirmed with a larger number of rats and additional behavioral analysis. Western blotting, rt-PCR and immunocytochemistry will be used to assay the effects of troglitazone on proinflammatory cytokines and growth factors that are likely candidates for modulating recovery following cerebral ischemia.

描述（由申请人提供）：中风是一种毁灭性疾病。我们迫切需要了解缺血性中风后的伤害和恢复机制，以设计将限制缺血性损伤并促进康复的治疗方法。炎症加剧了缺血性损伤，并可能在中风后的重塑和恢复中发挥作用。我们的长期目标是阐明炎症在急性和慢性时间范围中脑缺血中的作用。为了实现这一目标，我们建议使用具有抗炎特性的新药物，Ppargamma激动剂。 troglitazone是一种ppargamma激动剂，降低了促炎性细胞因子和其他炎症分子的表达。初步数据表明，在大鼠局灶性缺血后，曲霉素会降低梗塞大小，并且对促炎性细胞因子的免疫反应性在同一动物中降低。此外，我们表明脑缺血后ppargamma表达增加。这种增加在数小时内存在，并且持续至少一周。实验旨在使用其他ppargamma激动剂和拮抗剂测试ppargamma激活在神经保护中的作用。必须检查必须进行激活的时间段。我们建议将蛋白质印迹，定量RT-PCR和免疫细胞化学的结合使用，以分析炎症对观察到的神经保护的贡献。我们将通过施用阻断细胞因子，白介素Lβ和肿瘤坏死因子α以及troglitazone的化合物来特异性地检查促炎细胞因子的作用。我们建议进一步检查缺血性大脑中ppargamma的表达，并探索ppargamma激动剂对这种表达的影响。最后，探索了ppargamma激动剂在确定梗塞体积后调节功能结果的能力。初步数据表明，在局灶性中风后二十四小时零四天时，troglitazone可能会改善结果。当此时管理时，troglitazone不会降低梗塞大小。这些初步数据将通过大量大鼠和其他行为分析确认。蛋白质印迹，RT-PCR和免疫细胞化学将用于测定troglitazone对促炎细胞因子和生长因子的影响，这些因素可能是调节脑缺血后调节恢复的候选者。