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

摘要 足月儿和早产儿缺氧缺血(HI)所致脑损伤常导致慢性 神经和发育障碍，然而，只有有限的治疗方法可用于预防和 治疗。人绒毛膜促性腺激素(HCG)是一种胎盘来源的激素，具有以下生物学特性 使其适用于损伤新生儿大脑的神经保护。绒毛膜促性腺激素在结构和功能上的作用 作为一种免疫调节性神经营养素蛋白，促进幼体的存活、生长和分化 神经元。此外，hcg受体存在于胎儿神经系统中，hcg本身也可以进入血液。 大脑屏障并进入大脑。我们还发现，外周腹膜腔内注射这种激素 保护新生小鼠的大脑免受HI的影响。此外，人绒毛膜促性腺激素直接暴露于未成熟 受损神经元增加其存活和生长并保护其免受谷氨酸受体的影响 兴奋性毒性。然而，关于hCG的最大神经保护效果、安全性和细胞因子知之甚少。 负责其抗退化作用的机制。此外，人绒毛膜促性腺激素受体在脑出血中的作用 健康的和患病的发育中的大脑仍然未知。为了解决这一问题，我们建议使用 生化、分子、组织学、行为学和神经生理学方法探讨神经保护 人绒毛膜促性腺激素及其受体在早产和足月脑损伤小鼠模型中的作用。中心假说 该项目的主要内容是hCG激活受损足月和早产小鼠大脑的中枢hCG受体减少 并通过PKA/ERK介导的途径减少神经元变性。这项研究 可作为人绒毛膜促性腺激素和/或其预防和预防机制发展的可翻译平台 新生儿脑损伤带来的破坏性神经影响的治疗。

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.