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）是早产儿获得性脑损伤的最常见原因