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

描述(申请人提供)：脑缺氧缺血后的脑损伤是导致儿童死亡和残疾的主要因素。事实上，脑损伤后的高质量生存是危重儿童最大的不可逆转的未得到满足的需求，包括那些患有癌症等并存疾病的儿童。婴儿和儿童脑缺氧缺血的最常见原因是心脏骤停；然而，在许多其他疾病中，脑缺氧缺血对生活质量产生负面影响，包括创伤性脑损伤、中风、脑出血以及炎症性和神经退行性疾病。令人沮丧的发病率或死亡率和存活率直接与缺氧缺血性脑病(HIE)的程度相关-以及被认为是徒劳的护理，是最常见的结果。迫切需要强有力的疗法来预防和/或治疗心脏骤停后的脑缺氧缺血，并作为一系列其他疾病的结果。线粒体是缺氧缺血损伤的症结所在。在缺氧-缺血损伤后，线粒体产生有毒的自由基，直接攻击重要的细胞成分；处于几个关键细胞死亡途径的汇合点；以及强大的炎症介质。所有这些潜在的病理机制的核心是超生理活性氧物种(ROS)的产生，使线粒体产生的ROS成为HIE合乎逻辑和潜在有效的治疗靶点。到目前为止，针对ROS的策略主要集中在自由基清除剂或取代内源性抗氧化剂来抑制这些高活性化合物。令人失望的是，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RO的产生，而不是试图扑灭它们。针对线粒体的新型化合物包括与以下物质结合的“治疗有效载荷”：i)利用线粒体和细菌之间的共同祖先，在抗菌剂中使用对线粒体膜具有高亲和力的化学部分；或ii)利用电泳性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景的基于氮氧化物的线粒体靶向治疗药物库，这些药物主要作为电子清除剂发挥作用，与传统的抗氧化剂形成对比，从而防止ROS的形成。此外，我们独一无二地准备在我们的发育中大脑缺氧缺血模型中测试这些强大的线粒体靶向治疗，包括我们的临床相关的儿童窒息心脏骤停模型。本研究的目的是合成和开发新的线粒体靶向治疗药物，以有意义地改善患有脑缺氧缺血的婴儿和儿童的神经预后和生活质量。

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.