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: 10404106
• 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 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10404106
• 关键词: Address; Animals; Anti-Inflammatory Agents; Asphyxia Neonatorum; Behavioral; Biochemical; Biological; Blood - brain barrier anatomy; Brain; Brain Hypoxia-Ischemia; Brain Injuries; Cerebral Ischemia-Hypoxia; Cerebrum; Chorionic Gonadotropin; Chronic; Cognitive; 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 (Brain); Histologic; Hormones; Human; Human Chorionic Gonadotropin; In Vitro; Infant; Injections; Injury; Knockout Mice; LH Receptors; LIF gene; Life; Lipopolysaccharides; Luteinizing Hormone; MEKs; Measures; Mediating; Methods; Modeling; Molecular; Morbidity - disease rate; Mus; Neonatal; Neonatal Brain Injury; Nerve Degeneration; Nervous System Physiology; Nervous system structure; Neurologic; Neurologic Effect; Neuronal Injury; Neurons; Neuroprotective Agents; Newborn Infant; Pathway interactions; Peripheral; Pharmacology; Phosphotransferases; Pregnancy; Preterm brain injury; Prevention; Process; Property; Proteins; Receptor Activation; Research; Rice; Role; Safety; Seizures; Signal Pathway; Term Birth; Testing; Therapeutic Agents; Time; Vascular Endothelial Growth Factors; cerebral degeneration; clinically significant; disability; excitotoxicity; exposed human population; fetal; 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 therapeutics; premature; preterm newborn; pup; receptor; receptor function; small hairpin RNA; systemic inflammatory response; tissue injury; translational impact; treatment strategy

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.

抽象的 新生儿缺氧 - 疾病（HI）在该期间和早产新生儿脑损伤经常导致慢性 神经和发育障碍，但是，只有有限的疗法可用于预防和 治疗。人绒毛膜促性腺激素（HCG）是一种具有生物学特性的位置衍生的果 使其适合于受伤的新生大脑神经保护作用。 HCG在结构和功能上起作用 作为免疫调节的神经营养蛋白，增强了未成熟的生存，生长和分化 神经元。此外，在胎儿神经系统中发现了HCG受体，HCG本身可以跨越血液 大脑屏障并进入大脑。我们还发现该赛马的外周腹膜内给药 保护新生小鼠大脑免受HI的影响。此外，直接暴露于HCG未成熟 受伤的神经元增加了其生存和生长，并保护它们免受谷氨酸受体介导的侵害 兴奋性毒性。但是，关于HCG的最大神经保护效率，安全性和细胞的最大知识知之甚少 机制负责其抗变性效应。此外，脑HCG受体在 健康和厌恶的发育脑部的大脑仍然未知。为了解决这个问题，我们建议使用 生化，分子，组织学，行为和神经生理学方法探索神经保护作用 HCG和HCG受体在早产和脑损伤的小鼠模型中的功能。中心假设 这个项目的是，HCG在受伤的期限内通过HCG激活中央HCG受体，而早产小鼠脑则减少了 脑功能障碍并通过PKA/ERK介导的途径下降神经元变性。这项研究 可以作为开发HCG和/或其预防机制的可翻译平台 治疗新生儿脑损伤带来的毁灭性神经系统作用。