Therapeutic Strategies for Neonatal Hypoxic-Ischemiic Encephalopathy

新生儿缺氧缺血性脑病的治疗策略

基本信息

批准号：
9278273
负责人：
RAYMOND Charles KOEHLER
金额：
$ 41.37万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9278273
关键词：
3-nitrotyrosine Adult Aftercare Amides Animal Model Antioxidants Apoptosis Apoptotic Asphyxia Asphyxia Neonatorum Attenuated Behavior Behavioral Binding Birth Brain Brain Hypoxia-Ischemia CASP3 gene Cause of Death Cell Death Signaling Process Cell Nucleus Cells Cellular Stress Cerebrum Chemoprotective Agent Childhood Cleaved cell Cognitive Corpus striatum structure Cysteine Synthase DNA Data Deoxyguanosine Dose Encephalopathies Enzymes Erythroid Female Genes Glutamate-Cysteine Ligase Glutathione Glutathione S-Transferase Guidelines Heart Arrest Hippocampus (Brain)Hospitals Hour Human Hydroxyeicosatetraenoic Acids Hypoxia Hypoxic-Ischemic Brain Injury Infant Infant Mortality Inflammation Inflammatory Response Injection of therapeutic agent Injury Institutes Interleukin-1 beta Interleukin-8 Ligands Lipid Peroxidation Lipid Peroxides MK801 Metabolic Pathway Metabolism Microglia Modeling Morbidity - disease rate Morphology Motor Mus Necrosis Neonatal Neurologic Neurologic Deficit Neurons Newborn Animals Newborn Infant Nuclear Nuclear Translocation Outcome Oxidative Stress Perinatal Pharmaceutical Preparations Pharmacotherapy Phase Phosphotransferases Polymers Proteins RIPK1 gene RIPK3 gene RNA Response Elements Resuscitation Sensory Signal Transduction Societies Stroke Sulforaphane Survivors System TNF gene Term Birth Testing Thalamic structure Therapeutic Translations Traumatic Brain Injury Up-Regulation antioxidant enzyme clinically relevant cognitive disability cognitive function disability drug candidate experimental study functional outcomes glutathione peroxidase immunoreactivity improved induced hypothermia inhibitor/antagonist male natural hypothermia neonatal brain neonatal encephalopathy neonate neurobehavior neuroinflammation neuroprotection overexpression oxidative damage postnatal preclinical study prevent promoter public health relevance putamen response sigma receptors standard of care transcription factor

项目摘要

DESCRIPTION (provided by applicant): Despite overall improvements in infant mortality in recent decades, morbidity from birth asphyxia remains largely unchanged and causes a significant burden to society. Inducing hypothermia within 6 hours of birth is an accepted treatment for neonates that suffer hypoxic-ischemic (HI) brain injury, but it remains underutilized worldwide. Moreover, neurologic and cognitive disabilities persist into late childhood in many of those treated. Thus, a critical need persists to find other therapies to be used alone or with hypothermia. In a neonatal animal model of HI that results in cerebral injury similar to that observed in term newborns, we found in preliminary experiments that injection of the naturally occurring chemoprotectant sulforaphane or the synthetic triterpenoid CDDO-EA after HI injury provided more robust neuroprotection than ten other candidate drugs previously tested in this model. Remarkably, this protection exceeded that observed when hypothermia was initiated at a clinically relevant delay of 3-4 hours after HI. In adult models of stroke and brain trauma, sulforaphane and CDDO-EA cause translocation of the transcription factor Nrf2 to the nucleus, where it binds to the antioxidant response element on promoters of genes of multiple Phase II antioxidant and defense enzymes. Nrf2 activators are attractive neuroprotective candidates for neonatal HI because of their multipotent action in upregulating a network of antioxidant systems and downregulating the inflammatory response. In Aim 1, we will test various doses of sulforaphane and CDDO-EA in neonatal animals. Using the dose and drug with optimal neuroprotection, we assess a broad therapeutic window for neuroprotection with a detailed stereologic analysis of surviving neurons in the vulnerable sensorimotor cortex, putamen, sensory thalamus, and hippocampal CA3 regions. We will also assess neurologic deficits and cognitive function. Thus far, preliminary data indicate robust neuroprotection in males and females when the activators are administered 5 min or 1 h after HI. The neuroprotection is associated with behavioral improvements. In Aim 2, we will examine the ability of Nrf2 activators, in the setting of reoxygenation of the neonatal brain, to stimulate nuclear translocation of Nrf2 and to upregulate antioxidant enzymes that are critical for glutathione synthesis and its antioxidant activity. Furthermore, we will determine the degree to which the drug attenuates glutathione depletion, a critical antioxidant in neonatal HI, and whether treatment blunts markers of oxidative stress and reduces neuroinflammation. Because neurons in immature brain die by different forms of programmed necrosis and apoptosis in a region-specific manner, we will investigate whether Nrf2 activators ameliorate specific forms of cell death signaling. Because therapeutic hypothermia is becoming the standard of care, in Aim 3 we will test whether Nrf2 activators augment the efficacy of hypothermia. Data obtained from these detailed preclinical studies in accordance with the STAIR and RIGOR guidelines are expected to form the basis for possible translation of Nrf2 activators as a sole therapeutic or as an adjunct therapy to hypothermia for neonatal HI.

描述（由适用提供）：尽管近几十年来婴儿死亡率的总体改善，但窒息出生的发病率在很大程度上保持不变，并对社会造成了重大燃烧。在出生后6小时内诱导体温过低是对遭受低氧缺血（HI）脑损伤的新生儿的公认治疗方法，但仍未充分利用全世界。而且，在许多接受治疗的人中，神经系统和认知障碍持续到童年。这就是批判性的需求，以找到单独使用或与体温过低的其他疗法。在HI的新生儿动物模型中，导致脑损伤与新生儿中观察到的脑损伤相似，我们在初步实验中发现，注射天然发生的化学保护剂硫磷酸酯或HI损伤后HI损伤后的合成型CDDO-EA提供了比以前在此模型中进行的十个候选药物更强大的神经保护作用。值得注意的是，这种保护超出了在HI后3-4小时临床相关延迟下启动体温过低时观察到的。在中风和脑创伤的成年模型中，磺胺和CDDO-EA会导致转录因子NRF2转移到细胞核上，在该核与多个II期抗氧化剂和防御酶的启动子上结合到抗氧化剂反应元件上。 NRF2激活剂是新生儿HI的有吸引力的神经保护候选者，因为它们在上调抗氧化剂系统网络并下调炎症反应方面具有多能作用。在AIM 1中，我们将在新生动物中测试各种剂量的硫烷和CDDO-EA。使用具有最佳神经保护作用的剂量和药物，我们通过对脆弱的感觉运动皮层，putamen，感觉thalamus和Hippocampal CA3区域的生存神经元进行详细的立体分析来评估神经保护范围的广泛治疗窗口。我们还将评估神经系统缺陷和认知功能。当HI之后5分钟或1小时，当激活剂给予雄性和女性时，表明男性和女性的稳健神经保护作用的初步数据。神经保护与行为改善有关。在AIM 2中，我们将研究NRF2激活剂在新生大脑的重氧中，刺激NRF2的核易位并上调抗氧化酶的核转运，这对于谷胱甘肽合成至关重要，这对于谷胱甘肽合成至关重要。此外，我们将确定药物减弱谷胱甘肽耗竭的程度，新生儿HI中的临界抗氧化剂，以及治疗是否会钝化氧化应激标记并减少神经炎症。由于未成熟大脑中的神经元因区域特异性的不同形式的程序性坏死和凋亡而死亡，因此我们将研究NRF2激活剂是否可以改善特定形式的细胞死亡信号传导。由于治疗体温过低已成为护理标准，因此在AIM 3中，我们将测试NRF2激活剂是否会增强体温过低的有效性。根据楼梯和严格的准则，从这些详细的临床前研究获得的数据有望构成可能将NRF2激活剂作为唯一治疗或作为新生儿HI低温的辅助治疗的基础。