Osmotherapy in Acute Ischemic Stroke

渗透疗法治疗急性缺血性中风

• 批准号: 6906375
• 负责人: ANISH BHARDWAJ
• 金额: $ 37.81万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6906375
• 关键词: arginine vasopressin; blood brain barrier; blood osmolarity; brain edema; cerebral ischemia /hypoxia; dystrophin; genetically modified animals; laboratory mouse; laboratory rat; magnetic resonance imaging; osmotic pressure; pathologic process; protein protein interaction; saline; stroke; stroke therapy; therapy design /development; water channel

DESCRIPTION (provided by applicant): Cerebral edema associated with large hemispheric infarctions is frequently encountered in clinical practice and is a major cause of morbidity and mortality. Clinically, osmotherapy is the mainstay of medical management of cerebral edema associated with ischemic stroke. While mannitol has been the conventional osmotic agent of choice, its therapeutic efficacy is limited by several untoward side effects. A few experimental studies and clinical case series suggest that hypertonic saline (HS) is efficacious in the treatment of cerebral edema in some brain injury paradigms, but its effects in ischemic stroke are not well studied. The overall goal of this research proposal is to test the hypotheses that institution and maintenance of a hyper-osmolar state with HS is an important treatment of cerebral edema following experimental ischemic stroke. We will further utilize HS as a tool to delineate the complex interactions of aquaporins and ariginine-vasopressin (A VP) in the pathogenesis of ischemia-evoked cerebral edema. In Aim 1, we will define the most efficacious treatment paradigm with HS for cerebral edema following transient as well as permanent middle cerebral artery occlusion (MCAO). We will discern the optimal serum osmolality necessary for ameliorating cerebral edema and test the hypothesis, utilizing magnetic resonance imaging in vivo, that treatment duration, timing of withdrawal from therapy and integrity of the blood brain barrier determine anti-edema efficacy of HS in focal cerebral ischemia. Aim 2 will test the hypothesis that amelioration in brain edema with HS occurs via modulation of AQP4 in injured and contralateral non-ischemic brain following MCAO. We will determine if systemic osmolar changes a) alter 3erivascular localization of AQP4 in the brain and b) alter the evolution (rate and degree) of cerebral edema following MCAO in mice lacking alpha-syntrophin (alpha-syn -/-) (a component of the dystrophin protein complex required for perivascular localization of AQP4) as compared to wild type (WT) mice. Aim 3 will determine if AVP release plays a significant role in ischemia-induced cerebral edema and test the hypothesis that it serves as an important link in how HS attenuates brain edema via alterations in AQP4 following focal ischemia. Specifically, we will determine if plasma and brain AVP levels are a) modulated by changes in systemic osmolality with HS treatment, and b) are attenuated in alpha-syn -/-mice as compared to WT mice following focal cerebral ischemia. These studies 1) have important translational significance for treatment of cerebral edema in patients with large cerebral infarctions, 2) will enhance our understanding of the complex mechanisms of edema formation following ischemic stroke, and 3) provide insights into potential newer therapeutic targets and strategies.

描述（由申请人提供）：与大半球梗死相关的脑水肿经常在临床实践中遇到，这是发病率和死亡率的主要原因。在临床上，渗透疗法是与缺血性中风相关的脑水肿的医疗管理的中流。尽管甘露醇一直是常规的渗透剂，但其治疗功效受到多种不良副作用的限制。一些实验研究和临床病例系列表明，在某些脑损伤范式中，高渗盐水（HS）在治疗脑水肿方面有效，但其在缺血性中风中的作用尚未得到很好的研究。该研究建议的总体目标是检验假设，即用HS的机构和维持高渗透状态是对实验性缺血性中风后脑水肿的重要治疗方法。我们将进一步利用HS作为划定水氨基通道蛋白和阿里吉宁 - 瓦苏蛋白（A VP）的复杂相互作用的工具。在AIM 1中，我们将定义最有效的治疗范例，用于瞬时和永久性脑动脉闭塞（MCAO）后，用于HS的HS范围。我们将辨别改善脑水肿所必需的最佳血清渗透压，并测试假设，利用体内磁共振成像，治疗持续时间，从治疗中退出的时间和血液屏障的完整性的时间确定HS在局灶性体外障碍中的抗肿瘤功效缺血。 AIM 2将检验以下假设：MCAO后受伤和对侧非缺血性脑的AQP4在脑水肿中的改善发生。我们将确定全身性渗透性是否改变a）改变大脑中AQP4的3蠕虫性定位，b）在MCAO后MCAO后改变缺乏α-伴侣蛋白（alpha-syn的小鼠）（成分）（一个分量与野生型（WT）小鼠相比，AQP4的血管周期定位所需的肌营养不良蛋白蛋白复合物需要AIM 3将确定AVP释放是否在缺血诱导的脑水肿中起重要作用，并检验了以下假设，即它是HS如何通过局灶性缺血后AQP4改变HS减轻脑水肿的重要联系。具体而言，我们将确定血浆和大脑AVP水平是否是通过HS处理的全身性渗透压变化来调节的，而B）在α-Syn-/ - 小鼠中减弱了与局灶性大脑局部缺血后的WT小鼠相比。这些研究1）对于大脑梗死大的患者的脑水肿的治疗具有重要的翻译意义，2）将增强我们对缺血性中风后凝血体形成的复杂机制的理解，3）提供了对潜在的新型治疗靶标和策略的见解。