Neuroprotective Actions of hCG in a Mouse Model of Term and Preterm Brain Injury

hCG 在足月和早产脑损伤小鼠模型中的神经保护作用

• 批准号: 10621384
• 负责人: Rafael Galindo
• 金额: $ 34.45万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10621384
• 关键词: Address; Animals; Anti-Inflammatory Agents; Asphyxia Neonatorum; Behavioral; Biochemical; Biological; Brain; Brain Hypoxia-Ischemia; Brain Injuries; Cerebral Ischemia-Hypoxia; Cerebral cortex; Cerebrum; Chorionic Gonadotropin; Chronic; Cognitive; Corpus striatum structure; Cyclic AMP-Dependent Protein Kinases; Data; Dependence; Development; Developmental Disabilities; Differentiation and Growth; Disease; Dose; Drug Kinetics; Electroencephalography; Encephalitis; Evaluation; Exposure to; Fetus; Functional disorder; Genes; Glutamate Receptor; Growth; Health; Hippocampus; Histologic; Hormones; Human; Human Chorionic Gonadotropin; In Vitro; Infant; Injections; Injury; Knockout Mice; LH Receptors; LIF gene; Lipopolysaccharides; Luteinizing Hormone; MEKs; Measures; Mediating; Methods; Modeling; Molecular; Morbidity - disease rate; Mus; Neonatal; Neonatal Brain Injury; Nerve Degeneration; Nervous System; Nervous System Physiology; Neurologic; Neurologic Effect; Neuronal Injury; Neurons; Neuroprotective Agents; Newborn Infant; Pathway interactions; Peripheral; Phosphotransferases; Pregnancy; Preterm brain injury; Prevention; Process; Proliferating; Property; Proteins; Receptor Activation; Research; Rice; Role; Safety; Seizures; Signal Pathway; Testing; Therapeutic Agents; Time; Vascular Endothelial Growth Factors; blood-brain barrier crossing; cerebral degeneration; clinical translation; clinically significant; disability; excitotoxicity; exposed human population; fetal; immunoregulation; improved; in vivo; inhibitor; injured; innovation; intraperitoneal; knock-down; mouse model; neonatal hypoxic-ischemic brain injury; neonatal mice; neonate; neurobehavioral; neurobiological mechanism; neuronal survival; neurophysiology; neuroprotection; neurotrophic factor; newborn brain injury; novel; novel therapeutic intervention; novel therapeutics; pharmacologic; premature; preterm newborn; pup; receptor; receptor function; small hairpin RNA; systemic inflammatory response; tissue injury; translational impact

ABSTRACT Brain injury from neonatal hypoxia-ischemia (HI) in the term and preterm newborn often results in chronic neurological and developmental disability and yet, only limited therapies are available for its prevention and treatment. Human chorionic gonadotropin (hCG) is a placentally derived hormone with biological properties that make it suitable for its use in neuroprotection of the injured newborn brain. hCG structurally and functionally acts as an immunomodulating neurotrophin protein, enhancing the survival, growth and differentiation of immature neurons. Furthermore, hCG receptors are found in the fetal nervous system and hCG itself can cross the blood brain barrier and enter the brain. We also find that peripheral intraperitoneal administration of this hormone protects the newborn mouse brain against the effect of HI. Furthermore, direct exposure of hCG to immature injured neurons increases their survival and growth and protects them against glutamate receptor-mediated excitotoxicity. However, little is known about hCG’s maximal neuroprotective efficacy, safety and the cellular mechanisms responsible its anti-degenerative effects. Furthermore, the function of brain hCG receptors in the healthy and diseased developing brain remains unknown. To address this concern, we propose to use biochemical, molecular, histological, behavioral and neurophysiological methods to explore the neuroprotective function of hCG and hCG receptors in a mouse model of preterm and term brain injury. The central hypothesis of this project is that central hCG receptor activation by hCG in the injured term and preterm mouse brain reduces cerebral dysfunction and decreases neuronal degeneration via a PKA/ERK-mediated pathway. This research can serve as a translatable platform for the development of hCG and/or its mechanisms in the prevention and treatment of the devastating neurological effects brought on by neonatal cerebral injury.

摘要 足月新生儿和早产儿缺氧缺血（HI）引起的脑损伤常导致慢性脑损伤， 神经和发育残疾，然而，只有有限的治疗方法可用于预防， 治疗人绒毛膜促性腺激素（hCG）是一种胎盘来源的激素，具有生物学特性， 使其适用于损伤的新生儿脑的神经保护。hCG的结构和功能 作为一种免疫调节神经营养蛋白，增强未成熟的细胞的存活、生长和分化， 神经元此外，hCG受体存在于胎儿神经系统中，hCG本身可以穿过血液 脑屏障进入大脑。我们还发现，外周腹腔注射这种激素， 保护新生小鼠大脑免受HI的影响。此外，hCG直接暴露于未成熟的 损伤的神经元增加了它们的存活和生长，并保护它们免受谷氨酸受体介导的 兴奋性毒性然而，关于hCG的最大神经保护功效、安全性和细胞毒性知之甚少。 负责其抗退化作用的机制。此外，脑hCG受体在脑内的功能也有待进一步研究。 健康和患病的发育中的大脑仍然是未知的。为解决这个问题，我们建议采用 通过生物化学、分子生物学、组织学、行为学和神经生理学等方法， hCG和hCG受体在早产和足月脑损伤小鼠模型中的功能。核心假设 本项目的一个重要方面是，在受损的足月和早产小鼠脑中，hCG对中枢hCG受体的激活作用降低， 通过PKA/ERK介导的途径改善脑功能障碍并减少神经元变性。本研究 可以作为开发hCG和/或其预防和治疗糖尿病的机制的可翻译平台， 治疗新生儿脑损伤带来的毁灭性神经影响。

项目成果

Functional neuropathology of neonatal hypoxia-ischemia by single-mouse longitudinal electroencephalography.

• DOI: 10.1111/epi.17403
• 发表时间: 2022-12
• 期刊: EPILEPSIA
• 影响因子: 5.6
• 作者: Johnson, Kevin J.;Moy, Brianna;Rensing, Nicholas;Robinson, Alexia;Ly, Michael;Chengalvala, Ramya;Wong, Michael;Galindo, Rafael
• 通讯作者: Galindo, Rafael