Bilirubin oxidation and intracerebral hemorrhage

胆红素氧化与脑出血

• 批准号: 7163681
• 负责人: JOSEPH Floyd CLARK
• 金额: $ 7.68万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-15 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7163681
• 关键词: Bilirubin; oxidation; intracerebral; hemorrhage

Intracerebral hemorrhage (ICH) is a type of stroke caused by bleeding into the brain, which leads to significant death and disability. Secondary and delayed pathophysiologic events can contribute to the death and disability of the ICH patient. These events are characterized by a breakdown of the blood brain barrier, edema development and cell death in white and gray matter. We have recently discovered that following hemorrhage in the brain, a new molecular species, bilirubin oxidation species (BOXes), are produced within the hematoma during the first 24 hours following ICH. Importantly, the concentration of BOXes in the hematoma is the highest (approximately 20 \iM) that we have observed in any of our experimental and clinical evaluations thus far. This finding is especially significant since we have previously demonstrated that BOXes are cytotoxic and our preliminary data indicate that they can contribute to the pathophysiological events leading to brain injury following ICH. Our overall goal in this research project is to test the Hypothesis that BOXes are acutely generated within the hematoma and contribute to edema formation and perihematomal brain injury following ICH. To address this hypothesis we will use our porcine ICH model. In Aim #1 we will measure the concentration of BOXes in the hematoma and perihematomal brain tissue to define the time course of production. In Aim #2 we will add BOXes to the infused blood to produce the hematoma and assess the damage and examine the underlying pathogenesis observed following experimental ICH. In Aim #3 we will investigate the mechanism(s) for BOXes production by examining two biochemical pathways required to generate BOXes: bilirubin generation and oxidative stress. It is anticipated the inhibition of bilirubin production and/or antioxidants will decrease BOXes production in the hematoma. These studies are important because we believe that strategies designed to prevent BOXes production in the hematoma should provide a novel and beneficial therapeutic option for patients who have suffered an ICH.

脑出血（ICH）是一种由脑出血引起的中风， 严重的死亡和残疾。继发性和迟发性病理生理事件可导致死亡 以及ICH患者的残疾。这些事件的特征是血脑屏障的破坏， 白色和灰质中的水肿发展和细胞死亡。我们最近发现， 当脑出血时，脑内产生一种新的分子物质，胆红素氧化物质（BOXes）， 在ICH后的前24小时内发生血肿。重要的是，BOXes在细胞中的浓度 血肿是我们在我们的任何实验和临床研究中观察到的最高的（约20 μ M）。 临床评价至今。这一发现特别重要，因为我们以前已经证明， BOX是细胞毒性的，我们的初步数据表明，它们可以促进病理生理 ICH后导致脑损伤的事件。 在这个研究项目中，我们的总体目标是测试盒子是快速生成的假设 在血肿内，并有助于ICH后水肿形成和血肿周围脑损伤。到 为了解决这一假设，我们将使用我们的猪ICH模型。在目标#1中，我们将测量 血肿和血肿周围脑组织中的BOX，以确定产生的时间过程。目标#2 我们将在输注的血液中加入BOXes以产生血肿，评估损伤并检查 实验性ICH后观察到的潜在发病机制。在目标#3中，我们将研究 通过检查产生BOX所需的两种生化途径来研究BOX产生的机制： 胆红素生成和氧化应激。预期胆红素产生的抑制和/或 抗氧化剂将减少血肿中BOX的产生。 这些研究是重要的，因为我们相信，旨在防止BOXes生产的策略 血肿中的药物应该为患有脑出血的患者提供一种新颖且有益的治疗选择 ICH。