Mitochondria-Targeted Redox Therapy for Cerebral Ischemia in the Developing Brain

描述（由申请人提供）：脑缺氧缺血后的脑损伤是儿童死亡和残疾的主要原因。事实上，脑损伤后的高质量生存是重症儿童最大的不可逆转的未满足需求，包括那些患有癌症等合并症的儿童。婴儿和儿童脑缺氧缺血的最常见原因是心脏骤停;尽管脑缺氧缺血对许多其他疾病的生活质量产生负面影响，包括创伤性脑损伤、中风、脑出血以及炎症和神经退行性疾病。缺氧缺血性脑病（HIE）的严重程度和无效治疗是最常见的结局。迫切需要预防和/或治疗心脏骤停后以及作为许多其他疾病的结果的脑缺氧-缺血的稳健疗法。 缺氧缺血性损伤的关键是线粒体。在缺氧缺血后，受损的线粒体产生直接攻击重要细胞成分的有毒自由基;处于几个关键细胞死亡途径的汇合处;并且是炎症的强有力介质。所有这些潜在的病理机制的核心是活性氧（ROS）的超生理产生，使得神经元产生的ROS成为HIE的逻辑和潜在影响的治疗靶点。迄今为止，针对ROS的策略集中在自由基清除剂或替代内源性抗氧化剂以淬灭这些高活性化合物。令人遗憾的是，这些策略并没有转化为有效的治疗方法。需要一种范式转变的方法，例如防止ROS的产生，而不是试图淬灭它们。 靶向线粒体的新型化合物包括与以下缀合的“治疗有效载荷”：i）利用线粒体和细菌之间的共同祖先，在对线粒体膜具有高亲和力的抗菌剂中使用的化学部分;或ii）利用电泳性质和线粒体膜电位的阳离子部分。作为一个多学科的团队，我们有幸合成和开发了一个有前途的基于氮氧自由基的靶向治疗药物库，与传统的抗氧化剂相比，这些药物主要起电子清除剂的作用，从而防止ROS的形成。此外，我们还准备在发育中大脑的缺氧缺血模型中测试这些强大的线粒体靶向疗法，包括我们的儿科窒息性心脏骤停的临床相关模型。本研究的目的是合成和开发新的靶向治疗药物，以有意义地改善患有脑缺氧缺血的婴儿和儿童的神经功能结局和生活质量。

DESCRIPTION (provided by applicant): Brain damage after cerebral hypoxia-ischemia is a major contributor to death and disability in children. In fact, quality survival after brain injuryis the greatest irreversible unmet need in critically ill children, including those with co-morbiditie such as cancer. The most common cause of cerebral hypoxia-ischemia in infants and children is as a consequence of cardiac arrest; although, cerebral hypoxia-ischemia negatively impacts quality of life in many other diseases including traumatic brain injury, stroke, intracerebral hemorrhage, and inflammatory and neurodegenerative diseases. Disheartening morbidity or mortality with survivability directly related to the degree of hypoxic-ischemic encephalopathy (HIE)-and perceived futile care, are the most common outcomes. Robust therapies to prevent and/or treat cerebral hypoxia-ischemia after cardiac arrest and as a consequence of a host of other diseases are urgently needed. At the crux of hypoxia-ischemic injury, are mitochondria. After hypoxia-ischemia damaged mitochondria produce toxic free radicals that directly attack vital cellular constituents; are at the convergence of several critical cell death pathways; and ar powerful mediators of inflammation. Central to all of these potentially pathological mechanisms is the supraphysiologic generation of reactive oxygen species (ROS), making mitochondria-generated ROS a logical and potentially impactful therapeutic target for HIE. To date, strategies targeting ROS have focused on free radical scavengers or replacing endogenous antioxidants to quench these highly reactive compounds. Disappointingly, these strategies have not translated into efficacious treatments. A paradigm-shifting approach is needed, e.g. preventing generation of ROS, rather than attempting to quench them. Novel compounds that target mitochondria include "therapeutic payloads" conjugated with: i) chemical moieties utilized in antibacterial agents that have a high affinity for mitochondrial membranes, taking advantage of the shared ancestry between mitochondria and bacteria; or ii) a cationic moiety, taking advantage of electrophoretic properties and mitochondrial membrane potential. As a multidisciplinary team, we are in the fortunate position to synthesize and develop a library of promising nitroxide-based, mitochondria-targeting therapeutics that function primarily as electron scavengers-in contrast to traditional antioxidants, thus preventing formation of ROS. Furthermore, we are uniquely poised to test these powerful mitochondria- targeting therapies in our models of hypoxia-ischemia in the developing brain, including our clinically relevant model of pediatric asphyxial cardiac arrest. The aim of this research is to synthesize and develop novel mitochondria-targeting therapeutics, toward meaningfully improving neurological outcome and quality of life in infants and children suffering from cerebral hypoxia-ischemia.