Bilirubin oxidation and intracerebral hemorrhage

描述（由申请人提供）：脑出血（ICH）是一种由脑出血引起的中风，可导致严重的死亡和残疾。继发性和迟发性病理生理事件可导致ICH患者死亡和残疾。这些事件的特征在于血脑屏障的破坏、水肿发展和白色和灰质中的细胞死亡。我们最近发现，脑出血后，一种新的分子物质，胆红素氧化物质（BOX），在脑出血后的第一个24小时内产生的血肿。重要的是，血肿中BOX的浓度是迄今为止我们在任何实验和临床评价中观察到的最高的（约20 μ M）。这一发现尤其重要，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成导致ICH后脑损伤的病理生理事件。本研究项目的总体目标是验证以下假设：BOXes是在血肿内急性生成的，并有助于ICH后水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ICH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，以确定产生的时间过程。在目标#2中，我们将向输注的血液中添加BOX以产生血肿，并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，我们将通过检查生成BOX所需的2种生化途径来研究BOX生成的机制：胆红素生成和氧化应激。预计胆红素产生和/或抗氧化剂的抑制将减少血肿中BOXes的产生。这些研究是重要的，因为我们相信，旨在防止血肿中BOXes产生的策略应该为患有ICH的患者提供一种新的和有益的治疗选择。

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.