Neuroprotective Actions of Thiazolidinediones

描述(由申请人提供)： 中风是美国的第三大死因，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因为无法足够快地给予神经保护剂来拯救缺血的大脑。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，表明噻唑烷二酮(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药物，具有神经保护作用。重要的是，我们发现TZDS必须在再灌注前给药才能有效。这些药物在闭塞后三小时内给药有效，治疗是有益的，即使它会导致再灌注延迟。到目前为止的初步数据使用的是一种不适合在人类身上使用的腹膜内给药。这些研究旨在阐明TZD静脉给药的疗效，确定与缺血和再灌流时间有关的最佳剂量和有效窗口。我们还建议检测血清中对TZDS的反应增加的游离脂肪酸水平以及可溶性细胞间黏附分子(ICAM)和基质金属蛋白酶(MMP9)，它们可能作为TZD介导的疗效的生物标志物，并可能有助于这项工作在人类身上的翻译。此外，TZDS在雌性大鼠身上的疗效得到证实，雌性大鼠可能更能代表中风人群。 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以有效地减少损伤和改善神经功能。我们提出的研究旨在确定啮齿动物的最佳剂量范例，最终目的是将这些数据转化为人类试验。

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.