Magnesium Induced Developmental Neuroapoptosis

镁诱导发育性神经细胞凋亡

基本信息

批准号：
7340544
负责人：
WILLIAM H DRIBBEN
金额：
$ 16.15万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-01-01 至 2012-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7340544
关键词：
Address Age Agonist Anesthetics Animals Anticonvulsants Apoptosis Apoptotic BAX gene Biochemical Pathway Brain Calcium Channel Caspase Caspase Inhibitor Cell Culture Techniques Cell Death Cell Survival Cells Cellular Membrane Cessation of life Charge Childhood Clinical Culture Media Development Discipline of obstetrics Divalent Cations Dose Drug usage Eclampsia Electron Microscopy Electrophysiology (science)Ethanol Excitatory Amino Acid Antagonists Exposure to Fetus Fluorescent Probes Foundations Fura-2 Genes Hippocampus (Brain)Histological Techniques Human Image Immunohistochemistry In Vitro Intervention Ion Channel Knockout Mice Learning Magnesium Mediating Medicine Membrane Methods Mus N-Methyl-D-Aspartate Receptors N-Methylaspartate Nature Nerve Degeneration Neuroanatomy Neuronal Injury Neurons Pathway interactions Pattern Perinatal Exposure Pre-Eclampsia Pregnancy Premature Labor Process Property Proteins Public Health Rattus Reaction Research Research Personnel Rodent Screening procedure Series Sodium Channel Blockers Specificity Statistical Methods Supervision Surface Techniques Testing Time Toxicokinetics Transgenic Animals Western Blotting Wild Type Mouse Work caspase-3 caspase-8 fetal in vivo in vivo Model inhibitor/antagonist magfura-2 neurochemistry neuroprotection neurotoxic neurotoxicity neurotrophic factor prevent programs receptor research study response sedative synaptogenesis

项目摘要

DESCRIPTION (provided by applicant): Recent studies have demonstrated widespread apoptotic neurodegeneration induced in the developing rodent brain by transient exposure to various agents that suppress neuronal activity, including NMDA glutamate antagonists, GABAA agonists, ethanol, and sodium channel blockers. The potential neurotoxic effects of MgSO4 have important public health implications due to its frequent use in obstetrics for preterm labor and pre-eclampsia/eclampsia resulting in fetal exposure during the synaptogenic period. Although Mg++ has been used in obstetrics for over 60 years, there is a lack of studies addressing the effects of increased Mg++ on the fetal brain. Mg++ has inhibitory properties at numerous cellular membrane receptors and ion channels, and can enhance surface charge screening effects. I have developed preliminary in vivo evidence that exposure to Mg++ can trigger apoptotic neurodegeneration in the developing rodent brain. In order to expand upon these in vivo findings, I have performed experiments exposing cultured hippocampal neurons to Mg++ and found similar neurodegenerative effects. I hypothesize that because of its intrinsic neuroinhibitory properties, Mg++ at non-physiologically high concentrations can suppress neuronal activity to a degree that is sufficient to precipitate neuroapoptosis. The Aims of the proposed research are: 1) to further characterize the neurodegenerative reaction induced in the developing mouse brain by Mg++ with respect to nature, pattern, pattern, time-course and age specificity; 2) determine dose-response parameters in vitro and in vivo, including lowest effective dose, and compare this with doses to which the developing human brain is sometimes exposed; 3) investigate mechanisms(s) and protective strategies in both in vitro and in vivo models. In the course of this work I will learn various histological methods, including electron microscopy and immunohistochemistry; stereologic techniques to quantitate neuronal injury; western blotting for evaluating biochemical pathways; transgenic animals, electrophysiology, and Ca++ and Mg++ imaging to aid in mechanistic studies; and pharmacological interventions to evaluate protective strategies. In addition, I will develop an understanding of neuroanatomy, neurochemistry, toxicokinetics and toxicodynamics, and statistical methods. My preceptors, Dr. John Olney, Dr. Eugene Johnson and Dr. Steve Mennerick, will provide close guidance and supervision during the proposed research period.

描述（由申请人提供）：最近的研究表明，通过短暂接触各种抑制神经元活动的药物，包括 NMDA 谷氨酸拮抗剂、GABAA 激动剂、乙醇和钠通道阻滞剂，可在发育中的啮齿动物大脑中诱导广泛的细胞凋亡神经变性。 MgSO4 的潜在神经毒性作用具有重要的公共卫生影响，因为它在产科中经常用于早产和先兆子痫/子痫，导致胎儿在突触发生期间暴露。尽管 Mg++ 在产科中的应用已有 60 多年的历史，但缺乏研究探讨增加 Mg++ 对胎儿大脑的影响。 Mg++ 对许多细胞膜受体和离子通道具有抑制特性，可以增强表面电荷屏蔽作用。我已经开发出初步的体内证据，表明接触 Mg++ 可以引发发育中的啮齿动物大脑的细胞凋亡性神经变性。为了扩展这些体内发现，我进行了将培养的海马神经元暴露于 Mg++ 的实验，并发现了类似的神经退行性效应。我推测，由于其固有的神经抑制特性，非生理高浓度的 Mg++ 可以抑制神经元活动，达到足以促进神经细胞凋亡的程度。本研究的目的是： 1) 进一步表征 Mg++ 在发育中的小鼠大脑中诱导的神经退行性反应的性质、模式、模式、时间过程和年龄特异性； 2）确定体外和体内的剂量反应参数，包括最低有效剂量，并将其与发育中的人脑有时暴露的剂量进行比较； 3）研究体外和体内模型的机制和保护策略。在这项工作的过程中，我将学习各种组织学方法，包括电子显微镜和免疫组织化学；定量神经元损伤的立体学技术；用于评估生化途径的蛋白质印迹；转基因动物、电生理学以及 Ca++ 和 Mg++ 成像以辅助机制研究；和药物干预来评估保护策略。此外，我还将加深对神经解剖学、神经化学、毒代动力学和毒效动力学以及统计方法的了解。我的导师约翰·奥尔尼博士、尤金·约翰逊博士和史蒂夫·门纳里克博士将在拟议的研究期间提供密切的指导和监督。