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亡原因，治疗方案有限。神经保护剂的临床试验未能表现出功效，并且认为这种失败是由于无法迅速施用神经保护剂来挽救缺血性大脑。我们需要开发疗法以减少缺血性损伤并扩展治疗窗口以进行神经保护。我们描述了我们在大鼠脑缺血模型中获得的令人兴奋的初步数据，该模型表明，已经批准用于2型糖尿病的FDA的一类药物噻唑烷二酮（TZDS）是神经保护性的，该类别已批准用于2型糖尿病，目前正在研究中。重要的是，我们发现必须在再灌注之前对TZD进行管理才能有效。这些药物在闭塞后长达三个小时时，这些药物也有效，即使治疗会导致再灌注延迟。迄今为止的初步数据利用腹膜内给药，不适合在人类中使用。这些研究旨在阐明疗效IV TZD给药，定义最佳剂量和与缺血时间和再灌注有关的功效窗口。我们还建议检查自由脂肪酸的血清水平，这些脂肪酸的水平对TZD和可溶性细胞间粘附分子（ICAM）和基质金属蛋白酶（MMP）-9的响应，可以用作TZD介导的效力的生物标志物，并可能有助于将这项工作转化为人类。此外，在雌性大鼠中确认了TZD的功效，这可能更像是中风的人群。 公共卫生相关性： 中风是一种毁灭性的疾病，治疗方案有限。虽然噻唑烷二酮已经被FDA批准用于治疗2型糖尿病，但我们发现它们在减少损伤和改善动物模型中的神经系统功能方面有效。我们提出的研究旨在定义啮齿动物中最佳的给药范例，最终将这些数据转化为人类步道。