Bilirubin oxidation and intracerebral hemorrhage

描述(申请人提供)：脑出血(ICH)是一种由脑出血引起的中风，导致严重的死亡和残疾。继发性和延迟性病理生理事件可能导致脑出血患者的死亡和残疾。这些事件的特点是血脑屏障的破坏，白质和灰质中的水肿发展和细胞死亡。我们最近发现，脑出血后，在脑出血后的头24小时内，血肿内会产生一种新的分子物种--胆红素氧化物种(BOX)。重要的是，血肿中BOX的浓度是迄今为止我们观察到的所有实验和临床评估中最高的(约20Im)。这一发现特别重要，因为我们之前已经证明了BOX具有细胞毒性，并且我们的初步数据表明，它们可以促进脑出血后导致脑损伤的病理生理事件。我们在这项研究项目中的总体目标是检验这一假设，即BOX在血肿内急剧生成，并有助于脑出血后浮肿形成和血肿周围脑损伤。为了解决这一假设，我们将使用我们的猪脑出血模型。在目标1中，我们将测量血肿和血肿周围脑组织中BOX的浓度，以确定生产的时间进程。在目标2中，我们将向输注的血液中添加盒子以产生血肿，评估损伤并检查实验性脑出血后观察到的潜在发病机制。在目标3中，我们将通过检测产生BOX所需的两条生化途径来研究BOX产生的机制(S)：胆红素的产生和氧化应激。预计抑制胆红素的产生和/或抗氧化剂将减少血肿中胆红素的产生。这些研究很重要，因为我们相信，旨在防止血肿中产生BOX的策略应该为遭受脑出血的患者提供一种新的、有益的治疗选择。

DESCRIPTION (provided by applicant): 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 indicates 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 2 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.