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（HI）脑病（HIE）是早产儿和早产儿获得性脑损伤的最常见原因 足月婴儿会导致终生发病。每年有多达 100 万婴儿因接受治疗而患有 HIE 低体温 (TH) 为那些能够获得 TH 的人提供了强大的生存益处。促红细胞生成素也被证明 单独使用或与 TH 一起使用均有效。然而，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且口服的治疗方法 生物利用度一直难以捉摸。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即将进行的治疗。一种针对 HIE 的延迟且易于实施的疗法将 每年改变 100 万儿童的未来。 HIE 患者的长期随访揭示了永久性的 学习和记忆缺陷、缺乏认知灵活性和执行功能障碍。以前的 MRI 研究 患有新生儿脑损伤的婴儿揭示了胆碱能基底前脑（cBF）的退化，发生于 学习和记忆缺陷以及执行功能差。 cBF 对于正常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 是一个有趣且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 会导致 cBF 中的胆碱能神经元变性 和纹状体。 HI 后 1 个月，这些胆碱能神经元与前脑一起进入退行性状态 我们发现新生儿 HI 模型的认知灵活性较差。很多都是已知的 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有一个延长的前驱期退化阶段，可以接受治疗， 一种针对胆碱能神经变性的药物正在进行成人人体试验。 LM11A-31 是一种口服生物可利用的 p75NTr 功能调节剂，抑制其神经退行性特性并增强其 特别是在 cBF 中的神经保护作用。根据当前数据，我们假设开始治疗 新生儿 HI 后使用 LM11A-31 将挽救或预防 cBF 中胆碱能神经元的变性， 防止大脑皮层胆碱能输入的退化，从而改善学习、记忆和认知。 我们通过使用高通量行为触摸屏测试系统来解决这个假设，该系统检测 学习和记忆缺陷，快速确定 LM11A-31 疗效。我们的目标是 1：评估 发育中的小鼠大脑中的 LM11A-31 及其对整个大脑的新生儿 HI 病理学的影响， 尤其是在新生儿 HI 后 4 天至 10 周内给予受伤的 cBF 时。 2：确定 HI 后 4 天至 10 周使用 LM11A-31 是否可以改善视觉辨别力 HI 后 3-6 个月测试逆转学习，以及这是否与 cBF 的救援相关。