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）：中风是一种毁灭性的疾病。我们迫切需要了解缺血性卒中后的损伤和恢复机制，以便设计限制缺血性损伤和促进恢复的治疗方法。炎症加剧缺血性损伤，并可能在卒中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脑缺血中的作用。为了实现这一点，我们建议使用一类新的药物，PPARgamma激动剂，具有抗炎特性。曲格列酮是一种PPAR γ激动剂，可降低促炎细胞因子和其他炎症分子的表达。初步数据显示，曲格列酮可减少大鼠局灶性缺血后的梗死面积，并且在相同动物中，对促炎细胞因子的免疫反应性降低。此外，我们表明，PPARgamma表达增加脑缺血。这种增加在数小时内出现，并持续至少一周。设计实验以测试使用另外的PPARgamma激动剂和拮抗剂的PPARgamma活化在神经保护中的作用。将检查激活必须发生的时间段。我们建议使用Western印迹，定量RT-PCR和免疫细胞化学的组合来分析炎症对所观察到的神经保护的贡献。我们将通过给经历大脑中动脉闭塞的动物施用阻断细胞因子、白细胞介素-1 β和肿瘤坏死因子α的化合物沿着曲格列酮来具体检查促炎细胞因子所起的作用。我们建议进一步研究PPARgamma在缺血脑中的表达，并探讨PPARgamma激动剂对这种表达的影响。最后，研究了在确定梗死体积后，PPARgamma激动剂调节功能结果的能力。初步数据表明，曲格列酮可改善局灶性卒中后24小时和4天的预后。此时给药时，曲格列酮不会减少梗死面积。这些初步数据将通过大量大鼠和额外的行为分析进行确认。将使用蛋白质印迹法、rt-PCR和免疫细胞化学来测定曲格列酮对促炎细胞因子和生长因子的影响，这些促炎细胞因子和生长因子可能是调节脑缺血后恢复的候选因子。