Deferoxamine therapy for intracerebral hemorrhage

描述（由申请人提供）：自发性脑出血（ICH）是一种常见且经常致命的中风亚型。如果患者在休克中幸存下来，脑实质内的血肿会引发一系列事件，导致继发性损伤和严重的神经功能缺损。虽然人类的血肿逐渐消退，但脑出血患者的神经功能缺损通常是永久性和致残的。大鼠和猪的可重复性脑出血模型已被广泛用于研究脑损伤机制。我们已经开发了行为测试，可以检测长期的神经功能缺陷，我们和其他人发现在脑出血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。本转化项目的目的是阐明大鼠和猪脑出血后去铁胺治疗的最佳剂量和治疗时间窗。在一个特征良好的大鼠脑出血模型中，去铁胺将被全身给予。脑水肿形成、脑萎缩和神经功能缺损将作为终点进行检查。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)大鼠的最佳剂量/浓度在特征良好的猪脑出血模型中是否有效，以及4)是否可以在猪身上找到治疗时间窗。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益的建议。我们研究的长期目标是建立一种新的、急需的治疗人类脑出血的方法

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