The Role of PPAR Agonists in Inflammation and stroke

描述(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损伤和恢复的机制，以便设计出限制缺血性损伤和促进恢复的治疗方法。炎症加重了缺血性损伤，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，PPARγ激动剂，它具有抗炎特性。曲格列酮是一种PPARγ激动剂，可以减少促炎细胞因子和其他炎症分子的表达。初步数据显示，曲格列酮缩小了大鼠局灶性脑缺血后的梗塞面积，并且在相同的动物中，对促炎细胞因子的免疫反应性降低。此外，我们还发现，脑缺血后PPARGamma的表达增加。这种增加在几个小时内就会出现，并持续至少一周。实验旨在使用额外的PPAR伽马激动剂和拮抗剂来测试PPAR伽马激活在神经保护中的作用。将检查必须发生激活的时间段。我们建议使用免疫印迹、定量RT-PCR和免疫细胞化学相结合的方法来评估炎症对观察到的神经保护的贡献。我们将通过给予阻断细胞因子的化合物IL-Lβ和肿瘤坏死因子α以及曲格列酮来具体研究促炎细胞因子在大脑中动脉闭塞动物中所起的作用。我们建议进一步研究PPARGamma在脑缺血中的表达，并探讨PPARGamma激动剂对其表达的影响。最后，对PPARγ激动剂在确定梗塞体积后调节功能结果的能力进行了探讨。初步数据表明，在局灶性卒中后24小时和4天内给予曲格列酮可能会改善预后。此时给药，曲格列酮并不能缩小梗塞面积。这些初步数据将通过更多的老鼠和额外的行为分析来证实。Western blotting、RT-PCR和免疫细胞化学将用于检测曲格列酮对可能调节脑缺血后恢复的促炎细胞因子和生长因子的影响。

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.