Neuroprotective Actions of Thiazolidinediones

描述（由申请人提供）： 中风是美国第三大死亡原因，治疗选择有限。神经保护剂的临床试验未能显示功效，并且认为这种失败是由于不能足够快地施用神经保护剂以拯救缺血性脑。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。我们描述了我们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（TZDs）是一类药物，已被FDA批准用于2型糖尿病，目前正在研究作为中风的二级预防剂，具有神经保护作用。重要的是，我们发现TZD必须在再灌注前给药才能有效。这些药物在闭塞后3小时内给药是有效的，即使它会导致再灌注延迟，治疗也是有益的。迄今为止的初步数据使用了不适合用于人类的腹膜内给药。这些研究旨在阐明TZD IV给药的疗效，确定最佳剂量和与缺血和再灌注时间相关的疗效窗口。我们还建议检查血清中游离脂肪酸的水平，这些游离脂肪酸在对TZD和可溶性细胞间粘附分子（ICAM）和基质金属蛋白酶（MMP）-9的反应中增加，这可能作为TZD介导的疗效的生物标志物，并可能有助于将这项工作转化为人类。此外，TZD的疗效在雌性大鼠中得到证实，这可能更接近于卒中人群。 公共卫生相关性： 中风是一种毁灭性的疾病，治疗选择有限。虽然噻唑烷二酮类药物已经被FDA批准用于治疗2型糖尿病，但我们发现它们在动物模型中可有效减少损伤并改善神经功能。我们提出的研究，旨在确定最佳的剂量模式，在啮齿动物与最终的目的是将这些数据转化为人类的踪迹。

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.