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（由申请人提供）：尽管近几十年来婴儿死亡率总体较高，但出生窒息的发病率基本保持不变，并对社会造成重大负担。对于患有缺氧缺血的新生儿，在出生后 6 小时内诱导体温过低是一种公认的治疗方法。 HI）脑损伤，但仍未得到充分利用此外，许多接受治疗的人的神经系统和认知障碍持续到儿童晚期，因此，仍然迫切需要找到其他单独使用或与低温一起使用的治疗方法，以导致与脑损伤类似的HI新生儿模型。根据在足月新生儿中观察到的结果，我们在初步实验中发现，在 HI 损伤后注射天然存在的化学保护剂萝卜硫素或合成三萜类化合物 CDDO-EA 比之前在此模型中测试的其他十种候选药物提供了更强大的神经保护作用。值得注意的是，这种保护超过了在 HI 后 3-4 小时的临床相关延迟开始时观察到的保护作用。在成人中风和脑外伤模型中，萝卜硫素和 CDDO-EA 导致转录因子 Nrf2 易位到细胞核，其中。它与多种 II 期抗氧化剂和防御酶基因启动子上的抗氧化反应元件结合，由于其在新生儿 HI 中的多效作用，因此成为有吸引力的神经保护候选者。上调抗氧化系统网络并下调炎症反应在目标 1 中，我们将在新生动物中测试不同剂量的萝卜硫素和 CDDO-EA，使用具有最佳神经保护作用的剂量和药物，我们评估了神经保护的广泛治疗窗口。对脆弱的感觉运动皮层、壳核、感觉丘脑和海马 CA3 区域的幸存神经元进行详细的立体学分析到目前为止，我们还将评估神经功能缺陷和认知功能。数据表明，HI 后 5 分钟或 1 小时给予激活剂可对男性和女性产生强大的神经保护作用。在目标 2 中，我们将检查 Nrf2 激活剂在新生儿复氧情况下的能力。大脑，刺激 Nrf2 的核易位并上调对谷胱甘肽合成及其抗氧化活性至关重要的抗氧化酶。此外，我们将确定该药物的作用程度。减轻谷胱甘肽的消耗，谷胱甘肽是新生儿 HI 中的一种关键抗氧化剂，以及治疗是否会减弱氧化应激标志物并减少神经炎症。由于未成熟大脑中的神经元以区域特异性方式通过不同形式的程序性坏死和细胞凋亡而死亡，因此我们将研究 Nrf2 激活剂是否有效。改善特定形式的细胞死亡信号传导由于低温治疗正在成为护理标准，因此在目标 3 中我们将测试 Nrf2 是否存在。根据 STAIR 和 RIGOR 指南从这些详细的临床前研究中获得的数据预计将为 Nrf2 激活剂作为新生儿 HI 低温治疗的单一治疗或辅助治疗奠定基础。