Magnesium Induced Developmental Neuroapoptosis

镁诱导发育性神经细胞凋亡

• 批准号: 7772260
• 负责人: WILLIAM H DRIBBEN
• 金额: $ 16.18万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 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/7772260
• 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

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，通过短暂暴露于抑制神经元活性的各种药物，包括NMDA谷氨酸拮抗剂，Gabaa激动剂，乙醇，乙醇和钠通道阻滞剂，引起了发育中啮齿动物大脑中诱导的广泛凋亡神经退行性。 MGSO4的潜在神经毒性作用具有重要的公共卫生影响，因为它经常在妇产科中用于早产和子痫前期/eClampsia，导致突触时期导致胎儿暴露。尽管MG ++已在妇产科中使用了60多年，但缺乏研究Mg ++对胎儿大脑的影响的研究。 Mg ++在许多细胞膜受体和离子通道上具有抑制性能，并且可以增强表面电荷筛选效果。我已经开发了初步的体内证据，表明暴露于Mg ++可以触发发育中的啮齿动物大脑中的凋亡神经变性。为了扩展这些体内发现，我进行了实验，将培养的海马神经元暴露于Mg ++，并发现了类似的神经退行性作用。我假设，由于其内在的神经抑制性能，在非生理学上浓度高的Mg ++可以抑制神经元活性，以至于足以沉淀神经凋亡。拟议的研究的目的是：1）进一步表征Mg ++在自然，模式，模式，时间表和年龄特异性方面通过Mg ++引起的神经退行性反应； 2）在体外和体内确定剂量反应参数，包括最低有效剂量，并将其与有时会暴露于发育中的人脑的剂量进行比较； 3）研究体外和体内模型中的机制和保护策略。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，以帮助机械研究；以及评估保护策略的药理干预措施。此外，我将对神经解剖学，神经化学，毒理学和毒理学和统计方法发展有所了解。我的主持人约翰·奥尔尼（John Olney）博士，尤金·约翰逊（Eugene Johnson）博士和史蒂夫·梅纳尼克（Steve Mennerick）博士将在拟议的研究期间提供密切的指导和监督。