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。我们不得不了解伤害和康复的机制 以下缺血性中风，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 慢性时间框架。为此，我们建议使用新的药物，ppargamma激动剂， 具有抗炎特性。 troglitazone是一种ppargamma激动剂，降低了 促炎细胞因子和其他炎症分子。初步数据显示troglitazone 减少大鼠局灶性缺血后的梗塞大小，并针对促炎的免疫反应性 同一动物中的​​细胞因子降低。此外，我们表明ppargamma表达增加了 脑缺血之后。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激动剂和对手。必须检查必须进行激活的时间段。 我们建议将Western印迹，定量RT-PCR和免疫细胞化学的结合使用 测定炎症对观察到的神经保护作用的贡献。我们将专门检查角色 通过促炎细胞因子施加的通过施用阻断细胞因子的化合物，白介素 - lbeta 和肿瘤坏死因子α以及troglitazone到接受大脑中动脉的动物 阻塞。我们建议进一步检查ppargamma在缺血性大脑中的表达，并探索 ppargamma激动剂对这种表达的影响。最后，ppargamma激动剂调节的能力 探索了确定梗塞体积的时间后的功能结果。初步数据 这表明troglitazone在管理二十四小时四天时可能会改善结果 局灶性中风后。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。西 将使用吸墨性，RT-PCR和免疫细胞化学来分析troglitazone对 促炎的细胞因子和生长因子可能是调节恢复卵头的候选者 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.