Cholinergic neuron degeneration after HI: New target for delayed therapy of neonatal HI to improve Learning and Memory Deficits

HI 后胆碱能神经元变性：新生儿 HI 延迟治疗改善学习和记忆缺陷的新目标

• 批准号: 10451058
• 负责人: FRANCES J NORTHINGTON
• 金额: $ 24.56万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-15 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10451058
• 关键词: Acute; Address; Adult; Affect; Arousal; Behavioral; Birth; Brain; Brain Injuries; Caring; Cell Death; Cerebrum; Child; Cognition; Cognitive; Cold Chains; Complex; Core-Binding Factor; Corpus striatum structure; Data; Decision Making; Development; Discrimination Learning; Disease; Drug Targeting; Encephalopathies; Erythropoietin; Executive Dysfunction; Face; Formulation; Functional disorder; Future; Human; Hypoxia; Impaired cognition; Infant; Injections; Injury; Learning; Life; Longterm Follow-up; Magnetic Resonance Imaging; Medical; Memory; Memory impairment; Modeling; Morbidity - disease rate; Mus; NGFR Protein; Neonatal; Neonatal Brain Injury; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Neuropsychology; Oral; Oral cavity; Outcome; Pathologic; Pathology; Patients; Pharmaceutical Preparations; Phase; Phenotype; Premature Infant; Property; Prosencephalon; Refrigeration; Research; Resources; Rest; Reversal Learning; Rodent; Safety; School-Age Population; Signal Transduction; Stream; Survivors; System; Testing; Therapeutic; Time; Treatment Efficacy; Visual; basal forebrain; base; brain cell; cholinergic; cholinergic neuron; cognitive disability; cost; disability; executive function; flexibility; hypoxia neonatorum; hypoxic ischemic injury; improved; injured; innovation; natural hypothermia; neonatal care; neonatal hypoxic-ischemic brain injury; neural network; novel; novel therapeutics; prevent; receptor; safety testing; small molecule; therapeutic target; touchscreen

Hypoxic-ischemic (HI) encephalopathy (HIE), the most frequent cause of acquired brain injury in preterm and term infants causeslife-long morbidity. As many as 1 million infants/year suffer HIE with therapeutic hypothermia (TH) affording a strong survival benefit in those with access to TH. Erythropoietin is also proving effective both alone and with TH. However, both therapies must be started early. Despite significant progress in neonatal HI injury research, a therapy that is effective beyond the acute phase of the disease and is orally bioavailable has been elusive. Most babies affected by HIE have no access NICU care, TH, Epo or any other upcoming therapies within the necessary time frames. A delayed, easily administered therapy for HIE would change the future for 1 million children each year. Long term follow-up of HIE patients reveals permanent learning and memory deficits, lack of cognitive flexibility, and executive dysfunction. MRI studies of former infants with neonatal brain injury reveals degeneration in the cholinergic basal forebrain (cBF), occurring with learning and memory deficits and poor executive function. The cBF is essential for proper executive function, cognitive flexibility, learning and memory, arousal, spatial learning, decision-making, modulation of cortical activity and the default mode network. The cBF is an interesting and novel potential therapeutic target for neonatal HI because we now show that neonatal HI precipitates cholinergic neuronal degeneration in the cBF and striatum. These cholinergic neurons enter a degenerative state 1 month after HI in concert with forebrain injury and prior to time at which we find poor cognitive flexibility in the neonatal HI model. Much is known about degeneration of cholinergic neurons in adult neurodegenerative diseases. Importantly, cholinergic neurons have an extended prodromal phase of degeneration prior to cell death that is amenable to therapy, and a drug targeting cholinergic neurodegeneration is in adult human trials. LM11A-31 is an orally bioavailable modulator of p75NTr function that suppresses its neurodegenerative properties and enhances its neuroprotective actions specifically in the cBF. Based on current data, we hypothesize that initiating treatment with LM11A-31 after neonatal HI will rescue or prevent degeneration of cholinergic neurons in the cBF and prevent degeneration of cholinergic input to the cortex resulting in improved learning, memory, and cognition. We address the hypothesis by using a high through-put behavioral touchscreen testing system, that detects learning and memory deficits, to rapidly determine LM11A-31 efficacy. Our Aims are 1: To assess the effect of LM11A-31 in the developing mouse brain and its effect on pathology of neonatal HI throughout the brain, especially in the injured cBF, when given from 4 days to 10 weeks after neonatal HI. And 2: Determine whether use of LM11A-31 from 4 days-10 weeks after HI improves visual discrimination and reversal learning tested 3-6 months after HI and whether this correlates with rescue of the cBF.

缺氧缺血性脑病（HIE）是早产儿和新生儿获得性脑损伤的最常见原因， 足月儿导致终生发病。每年有多达100万婴儿患有HIE， 低温（TH）在那些获得TH的人中提供了强大的生存益处。促红细胞生成素也证明了 单独和与TH一起有效。但是，这两种疗法都必须尽早开始。尽管取得了重大进展 在新生儿HI损伤研究中，一种在疾病急性期后有效的治疗方法， 生物可利用性一直难以捉摸。大多数受HIE影响的婴儿无法获得NICU护理，TH，Epo或任何其他护理。 在必要的时间范围内进行治疗。一种延迟的、容易实施的治疗HIE的方法， 每年改变100万儿童的未来。对HIE患者的长期随访显示， 学习和记忆缺陷、认知灵活性缺乏和执行功能障碍。MRI研究前 患有新生儿脑损伤的婴儿显示胆碱能基底前脑（cBF）变性， 学习和记忆缺陷以及执行功能差。cBF对正常的执行功能至关重要， 认知灵活性，学习记忆，唤醒，空间学习，决策，皮层调节 活动和默认模式网络。cBF是一个有趣的和新的潜在的治疗靶点， 新生儿HI，因为我们现在表明，新生儿HI沉淀cBF胆碱能神经元变性 和纹状体。这些胆碱能神经元在HI后1个月与前脑一致进入变性状态 损伤和之前的时间，在此之前，我们发现在新生儿HI模型认知灵活性差。多已知 关于成人神经退行性疾病中胆碱能神经元的退化。重要的是，胆碱能 神经元在细胞死亡之前具有延长的退化前驱期， 一种针对胆碱能神经变性的药物正在成人人体试验中。LM11A-31是一种口服生物可利用的 p75NTr功能的调节剂，抑制其神经变性性质并增强其 特别是在cBF中的神经保护作用。根据目前的数据，我们假设开始治疗 新生儿HI后用LM11A-31治疗将挽救或防止cBF中胆碱能神经元的变性， 防止皮层胆碱能输入的退化，从而改善学习、记忆和认知。 我们通过使用高吞吐量的行为触摸屏测试系统来解决这一假设，该系统检测 学习和记忆缺陷，以快速确定LM11A-31的功效。我们的目标是1：评估 LM11A-31在发育中小鼠脑中的作用及其对整个脑中新生儿HI病理学的影响， 尤其是在新生儿HI后4天至10周给予损伤的cBF。 和2：确定HI后4天-10周使用LM11A-31是否改善视觉辨别力 HI后3 - 6个月测试逆转学习，以及这是否与cBF的挽救相关。