Bilirubin oxidation and intracerebral hemorrhage

脑出血(ICH)是一种由脑出血引起的中风，导致 重大死亡和残疾。继发性和延迟性病理生理事件可能导致死亡。 以及ICH患者的残疾。这些事件的特点是血脑屏障的破坏， 白质和灰质的水肿发展和细胞死亡。我们最近发现以下情况 脑出血，一种新的分子物种，胆红素氧化物种(BOCKS)，是在 脑出血后24小时内的血肿。重要的是，箱子集中在 血肿是我们观察到的任何实验和实验中最高的(约20\IM) 到目前为止的临床评估。这一发现特别有意义，因为我们之前已经证明 BOX是细胞毒性的，我们的初步数据表明，它们可以在病理生理上做出贡献 导致脑出血后脑损伤的事件。 我们在这个研究项目中的总体目标是检验这样一个假设，即盒子是由 并导致脑出血后的水肿形成和血肿周围脑损伤。至 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 盒子在血肿和血肿周围的脑组织中定义了产生的时间进程。在目标#2中 我们将向输血中添加盒子以产生血肿，并评估损害并检查 实验性脑出血后观察到的潜在发病机制。在目标3中，我们将调查 盒子产生机制(S)，通过研究产生盒子所需的两条生化途径： 胆红素生成和氧化应激。预计胆红素的产生和/或抑制 抗氧化剂会减少血肿中盒子的产生。 这些研究很重要，因为我们认为，旨在防止盒子生产的策略 血肿内注射应该为患有急性脑出血的患者提供一种新的有益的治疗选择。 我也是。

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.