Delayed Neurodegeneration After 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。虽然人类的血肿在几个月内逐渐消退，但功能恢复是分级的，通常是不完全的。ICH患者的神经功能缺损是永久性和致残性的。 为了了解ICH诱导的脑损伤的潜在机制并评价治疗干预，已经开发了许多ICH动物模型。一种可重复的大鼠ICH模型，包括向尾状核输注自体血，已被广泛用于研究脑损伤的机制，特别是早期水肿形成。然而，很难找到人类ICH长期影响的相关性。然而，最近，我们已经开发出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。脑出血后这种长期和延迟性脑损伤的机制尚不清楚，但我们的初步数据表明铁过载和氧化应激的作用。我们拟检验以下假设：1）确定红细胞溶解后脑内铁超载是否在脑出血后脑萎缩和神经功能缺损延长中起关键作用。2)确定铁超载是否加重氧化应激，导致ICH后迟发性神经退行性变。 本课题旨在探讨脑出血后迟发性神经元变性的机制。我们研究的长期目标是限制出血性脑损伤。如果我们的假设是正确的，这些实验可能会导致新的治疗ICH限制铁超载或减轻氧化性脑损伤。

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 human gradually resolves within several months, restoration of function is graded and usually incomplete. The neurological deficits in ICH patients are permanent and disabling. To understand the underlying mechanisms of ICH-induced brain injury and to evaluate therapeutic interventions a number of animal models of ICH have been developed. A reproducible rat ICH model, involving infusion of autologous blood into the caudate, has been used extensively to study mechanisms of brain injury and, in particular, early edema formation. It has, though, been difficult to find correlates of the long-term effects of human ICH. Recently, however, 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. The mechanisms involved in this prolonged and delayed brain injury after ICH are as yet unknown, but our preliminary data suggest a role for iron overload and oxidative stress. We propose to test the following hypotheses: 1) To determine whether iron overload in the brain after red blood cell lysis plays a key role in brain atrophy and prolonged neurological deficits after ICH. 2) To determine whether iron overload aggravates oxidative stress which contributes to delayed neurodegeneration after ICH. The purpose of our project is to investigate the mechanisms of delayed neurodegeneration after ICH. The long-term goal of our studies is to limit hemorrhagic brain injury. If our hypotheses are correct, these experiments may lead to novel therapies for ICH by either limiting iron overload or attenuating oxidative brain injury.