Deferoxamine therapy for intracerebral hemorrhage

描述(由申请人提供)：自发性脑出血(ICH)是一种常见且往往致命的中风亚型。如果患者在癫痫发作中存活下来，脑实质内的血肿会触发一系列事件，导致二次侮辱和严重的神经功能障碍。虽然人类的血肿逐渐消失，但脑出血患者的神经功能障碍通常是永久性的和致残的。可复制的大鼠和猪脑出血模型已被广泛应用于脑损伤机制的研究。我们已经开发了可以检测长期神经缺陷的行为测试，我们和其他人发现在脑出血的动物模型中存在延迟性脑萎缩。我们最近的研究表明，铁超载在脑出血后脑损伤中起重要作用。特别是，我们发现全身应用铁络合剂去铁胺可以减轻成年雄性大鼠脑出血所致的脑损伤。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口。在一个特征良好的脑出血大鼠模型中，系统地给予去铁胺。脑水肿形成、脑萎缩和神经功能障碍将被检查为终点。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口。然后，我们将测试3)在大鼠身上的最佳剂量/浓度在具有良好特征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。翻译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脑出血建立一种新的、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