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。我们迫切需要了解损伤和恢复的机制

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.