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: 7158571
• 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 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7158571
• 关键词: Acute; Agonist; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Apoptotic; Area; Behavioral; Behavioral Assay; Binding; Biological Assay; Brain; Cell Death; Cells; Cerebral Ischemia; Chronic; Class; DNA Nucleotidylexotransferase; Data; Development; Disease; Evaluation; Functional disorder; Gene Expression; Genes; Growth Factor; Hour; Infarction; Inflammation; Inflammatory; Inflammatory Infiltrate; Inflammatory Response; Injury; Interleukin-6; Interleukins; Investigation; Ischemia; Ischemic Stroke; Label; Ligands; Mediating; Mediator of activation protein; Middle Cerebral Artery Occlusion; Modeling; Neurologic; Neurons; Nitric Oxide Synthase; Nuclear Receptors; Numbers; Outcome; PPAR gamma; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Play; Process; Property; Proteins; Range; Rattus; Reaction; Recovery; Recovery of Function; Role; Role playing therapy; Stroke; Techniques; Testing; Therapeutic; Time; Tissues; Tumor Necrosis Factor-alpha; United States Food and Drug Administration; Week; Western Blotting; activating transcription factor; acute stroke; caspase-3; cell type; cytokine; day; design; functional outcomes; immunocytochemistry; immunoreactivity; improved; inhibitor/antagonist; mRNA Expression; neuron loss; neuroprotection; protective effect; research study; size; stroke recovery; therapy design; troglitazone

Stroke is a devastating disease. We desparately 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, that have anti-inflammatory properties. Troglitazone, a PPARgamma agonist, reduces the expression of the proinflammatory cytokines and other inflammatory molecules. Preliminary data show that troglitazone reduces infarct size following focal ischemia in rats and that immunoreactivity against proinflammatory 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 proinflammatory cytokines by administering compounds that block the cytokines, interleukin-lbeta 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 followng cerebral ischemia.

中风是一种毁灭性的疾病。我们需要单独了解损伤和恢复的机制 在缺血性中风后，为了设计治疗方法，将限制缺血性损伤，促进康复。 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。 长期的时间框架。为了达到这一目的，我们建议使用一类新的药物，PPAR伽马激动剂， 具有抗炎作用的物质。PPARγ激动剂曲格列酮可减少 促炎症细胞因子和其他炎症分子。初步数据显示，曲格列酮 减少大鼠局灶性脑缺血后的脑梗塞范围和抗炎性免疫反应 同样的动物体内的细胞因子也减少了。此外，我们还发现PPARGamma的表达增加了 在脑缺血后。这种增加在几个小时内就会出现，并持续至少一周。 实验旨在测试PPAR伽马激活在神经保护中的作用，通过额外的 PPARGamma激动剂和拮抗剂。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 测定炎症对所观察到的神经保护的贡献。我们将具体审查这一角色 由促炎细胞因子发挥作用，通过给予阻断细胞因子的化合物，白介素1β 肿瘤坏死因子-α联合曲格列酮对大脑中动脉手术动物的影响 遮挡。我们建议进一步检测PPARGamma在脑缺血中的表达，并探讨其在脑缺血中的作用。 PPARγ激动剂对这一表达的影响。最后，PPARγ激动剂的调节能力 对梗塞体积确定后的功能结果进行了探讨。初步数据 这表明，曲格列酮在24小时和4天内给药可能会改善结果。 局灶性卒中后。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数量和额外的行为分析来证实。西式 采用印迹杂交、RT-PCR和免疫细胞化学方法检测曲格列酮对血管内皮细胞生长的影响。 促炎症细胞因子和生长因子可能是调节康复的候选因素 脑缺血。

项目成果

Extension of the neuroprotective time window for thiazolidinediones in ischemic stroke is dependent on time of reperfusion.

• DOI: 10.1016/j.neuroscience.2010.07.063
• 发表时间: 2010-10-27
• 期刊: NEUROSCIENCE
• 影响因子: 3.3
• 作者: Gamboa, J.;Blankenship, D. A.;Niemi, J. P.;Landreth, G. E.;Karl, M.;Hilow, E.;Sundararajan, S.
• 通讯作者: Sundararajan, S.