Deferoxamine therapy for intracerebral hemorrhage

描述（由申请人提供）：自发性脑内出血（ICH）是一种常见且往往致命的卒中亚型。如果患者在发作后存活，脑实质内产生的血肿会引发一系列事件，导致二次损伤和严重的神经功能缺损。虽然人类的血肿会逐渐消退，但ICH患者的神经功能缺损通常是永久性和致残性的。大鼠和猪的可复制ICH模型已被广泛用于研究脑损伤的机制。我们已经开发出了可以检测长期神经功能缺损的行为测试，我们和其他人发现在ICH动物模型中存在延迟性脑萎缩。我们最近的研究表明，铁超载在脑出血后的脑损伤中起重要作用。特别是，我们发现，全身给药的铁螯合剂去铁胺可以减少ICH诱导的成年雄性大鼠脑损伤。本翻译项目的目的是阐明去铁胺治疗大鼠和猪脑出血后的最佳剂量和治疗时间窗。在充分表征的ICH大鼠模型中，将全身给予去铁胺。将检查脑水肿形成、脑萎缩和神经功能缺损作为终点。我们将确定：1）老年雄性大鼠的最佳剂量; 2）老年雄性大鼠的治疗时间窗。然后，我们将测试3）大鼠中的最佳剂量/浓度是否在充分表征的ICH猪模型中有效，以及4）是否可以在猪中发现治疗时间窗。转化研究团队包括三名基础科学家和两名临床医生。NINDS项目工作人员在提案制定过程中提供了有用的建议。我们研究的长期目标是为人类ICH建立一种新的和急需的治疗方法

DESCRIPTION (provided by applicant): Spontaneous intracerebral hemorrhage (ICH) is a common and often fatal stroke subtype. If the patient survives the ictus, the resulting hematoma within brain parenchyma triggers a series of events leading to secondary insults and severe neurological deficits. Although the hematoma in humans gradually resolves, the neurological deficits in ICH patients are usually permanent and disabling. Reproducible ICH models in rats and in pigs have been used extensively to study mechanisms of brain injury. We have developed behavioral tests that can detect prolonged neurological deficits and we and others have found that there is delayed brain atrophy in animal models of ICH. Our recent studies demonstrate that iron overload plays an important role in brain injury following ICH. In particular, we found that systemic administration of the iron chelator deferoxamine can reduce ICH-induced brain injury in adult male rats. The purpose of this translational project is to elucidate an optimal dose and therapeutic time window for deferoxamine therapy in rats and pigs after ICH. In a well-characterized rat model of ICH, deferoxamine will be given systemically. Brain edema formation, brain atrophy and neurological deficits will be examined as endpoints. We will determine: 1) an optimal dose in aged male rats; 2) a therapeutic time window in aged male rats. We will then test 3) whether or not the optimal dose/concentration in rats is effective in a well- characterized pig model of ICH and 4) whether or not a therapeutic time window can be found in pigs. The translational research team includes three basic scientists and two clinicians. The NINDS program staff have provided helpful advice during the proposal development. The long-term goal of our studies is to establish a novel and much needed therapy for ICH in humans