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.

低氧 - 缺血性（HI）脑病（HIE），是早产和最常见的脑损伤原因 术语婴儿导致长期发病率。多达100万婴儿/年患有治疗性 体温过低（TH）在获得TH的人中具有强大的生存益处。红细胞生成素也证明了 单独和TH有效。但是，两种疗法必须早点开始。尽管取得了重大进展 在新生儿HI损伤研究中 生物利用是难以捉摸的。受Hie影响的大多数婴儿都没有访问NICU护理，TH，EPO或任何其他婴儿 在必要的时间范围内即将进行的疗法。延迟，容易治疗的Hie治疗将 每年改变100万儿童的未来。 HIE患者的长期随访显示永久 学习和记忆缺陷，缺乏认知灵活性以及执行功能障碍。 MRI研究以前 新生儿脑损伤的婴儿显示出发生胆碱能基础前脑（CBF）的变性 学习和记忆缺陷和执行功能不佳。 CBF对于适当的执行功能至关重要， 认知灵活性，学习和记忆，唤醒，空间学习，决策，皮质调节 活动和默认模式网络。 CBF是一个有趣而新颖的潜在治疗靶点 新生儿HI，因为我们现在表明新生儿HI沉淀在CBF中胆碱能神经元变性 和纹状体。这些胆碱能神经元在与前脑共同1个月后进入退化状态 受伤和在新生儿HI模型中发现认知灵活性不佳的时间之前。众所周知 关于成人神经退行性疾病中胆碱能神经元的变性。重要的是，胆碱能 神经元在细胞死亡之前具有延长的前驱阶段，可接受治疗， 成人人类试验中，靶向胆碱能神经退行性的药物。 LM11A-31是一种口头生物利用 p75ntr函数的调节剂抑制其神经退行性特性并增强其神经退行性特性 CBF专门在CBF中的神经保护作用。根据当前数据，我们假设该治疗 新生儿HI后使用LM11A-31，将营救或防止CBF中胆碱能神经元的变性 防止胆碱能输入对皮质的退化，从而改善学习，记忆和认知。 我们通过使用高的贯穿行为触摸屏测试系统来解决该假设，该系统检测到 学习和记忆缺陷，以快速确定LM11A-31功效。我们的目标是1：评估 发育中的小鼠大脑中的LM11A-31及其对整个大脑新生儿HI的病理的影响， 特别是在受伤的CBF中，新生儿HI后4天到10周。 和2：确定HI后4天10周的使用LM11A-31是否可以改善视觉歧视 在HI之后3-6个月测试了逆转学习，这是否与CBF的营救相关。