Neuroprotective Actions of Thiazolidinediones

噻唑烷二酮类药物的神经保护作用

• 批准号: 7693759
• 负责人: SOPHIA SUNDARARAJAN
• 金额: $ 17.17万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7693759
• 关键词: 2,4-thiazolidinedione; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Biological Markers; Brain; Cause of Death; Cerebral Ischemia; Clinical; Clinical Trials; Data; Disease; Dose; FDA approved; Failure; Female; Funding; Gelatinase B; Hour; Human; Infarction; Injury; Insulin Resistance; Intercellular Adhesion Molecules; Intervention; Intraperitoneal Injections; Intravenous; Ischemia; Laboratories; Ligands; Mediating; Middle Cerebral Artery Occlusion; Modeling; National Institute of Neurological Disorders and Stroke; Nervous System Physiology; Neuroprotective Agents; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Nuclear; Oral; Outcome; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Pioglitazone; Population; Principal Investigator; Protective Agents; Rattus; Relative (related person); Reperfusion Therapy; Rodent; Route; Serum; Stroke; Testing; Therapeutic; Thiazolidinediones; Time; Translating; Translations; United States; Work; disability; functional outcomes; improved; insulin sensitizing drugs; intraperitoneal; neuroprotection; programs; public health relevance; research study; response; rosiglitazone; therapy development; transcription factor

DESCRIPTION (provided by applicant): Stroke is the third leading cause of death in the United States and treatment options are limited. Clinical trials of neuroprotective agents have failed to show efficacy and it is believed that this failure is due to the inability to administer neuroprotective agents quickly enough to rescue ischemic brain. We need to develop therapies to reduce ischemic injury and extend the therapeutic window for neuroprotection. We describe exciting preliminary data we have obtained in a rat cerebral ischemia model suggesting that thiazolidinediones (TZDs), a class of drugs, already FDA approved for use in type 2 diabetes and currently under study as a secondary preventative agent for stroke, is neuroprotective. Importantly, we find that TZDs must be administered prior to reperfusion in order to be effective. These drugs are effective when administered up to three hours after occlusion, and treatment is beneficial, even if it causes a delay in reperfusion. Preliminary data to date utilize an intraperitoneal administration which is not suitable for use in humans. These studies aim to clarify the efficacy IV TZD administration, define optimal dose and the window of efficacy both related to time of ischemia and reperfusion. We also propose to examine serum levels of free fatty acids which increase in response to TZDs and soluble intercellular adhesion molecule (ICAM) and matrix metalloproteinase (MMP)-9, which may serve as biomarkers of TZD mediated efficacy and may aid in the translation of this work to humans. In addition the efficacy of TZDs is confirmed in female rats which may more closely represent the human population subject to stroke. PUBLIC HEALTH RELEVANCE: Stroke is a devastating disease with limited treatment options. While thiazolidinediones are already FDA approved for the treatment of type 2 diabetes, we have found that they are effective in reducing injury and improving neurologic function in an animal model. We propose studies aimed at defining optimal dosing paradigms in rodents with the eventual aim of translating these data to human trails.

描述（由申请人提供）： 中风是美国第三大死因，治疗选择有限。神经保护剂的临床试验未能显示出疗效，人们认为这种失败是由于无法足够快地施用神经保护剂来挽救缺血的大脑。我们需要开发治疗方法来减少缺血性损伤并延长神经保护的治疗窗口。我们描述了在大鼠脑缺血模型中获得的令人兴奋的初步数据，这些数据表明噻唑烷二酮类药物 (TZD) 具有神经保护作用，该类药物已被 FDA 批准用于治疗 2 型糖尿病，目前正在研究作为中风的二级预防剂。重要的是，我们发现 TZD 必须在再灌注前施用才能有效。这些药物在闭塞后三小时内给药是有效的，并且治疗是有益的，即使它会导致再灌注延迟。迄今为止的初步数据采用的是不适合用于人类的腹膜内给药。这些研究旨在阐明静脉注射 TZD 给药的疗效，确定与缺血和再灌注时间相关的最佳剂量和疗效窗口。我们还建议检查对 TZD 和可溶性细胞间粘附分子 (ICAM) 和基质金属蛋白酶 (MMP)-9 反应而增加的游离脂肪酸的血清水平，这可能作为 TZD 介导功效的生物标志物，并可能有助于将这项工作转化为人类。此外，TZD 的功效在雌性大鼠中得到证实，雌性大鼠可能更接近于中风人群。 公共卫生相关性： 中风是一种毁灭性疾病，治疗选择有限。虽然噻唑烷二酮类药物已获得 FDA 批准用于治疗 2 型糖尿病，但我们发现它们可以有效减少动物模型损伤并改善神经功能。我们提出的研究旨在确定啮齿类动物的最佳剂量范式，最终目的是将这些数据转化为人类试验。