Neurodevelopmental Apoptosis

神经发育细胞凋亡

• 批准号: 6984990
• 负责人: NURI B FARBER
• 金额: $ 36.34万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-06 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6984990
• 关键词: apoptosis; developmental neurobiology; dimethylsulfoxide; drug vehicle; environmental toxicology; infant animal; laboratory mouse; neural degeneration; neurotoxicology; neurotoxins; propylene glycols; synaptogenesis

DESCRIPTION (provided by applicant): This is a second revision of a previously submitted application (R01-ES012443-01). It has recently been shown that apoptotic neurodegeneration can be triggered in the in vivo developing rodent CNS by any of several classes of drugs that have in common the property of abnormally suppressing neuronal activity. The period of vulnerability coincides with synaptogenesis, also known as the brain growth spurt period, which occurs postnatally in rodents (first 2 weeks after birth) and both prenatally and postnatally in humans (third trimester and several years after birth). Included among the offending agents are drugs that block NMDA glutamate receptors, drug that hyperactivate GABAA receptors and ethanol, which has both NMDA antagonist and GABAmimetic properties. The apoptogenic action of ethanol is a promising candidate to explain the reduced brain mass and neurobehavioral disturbances associated with the human Fetal Alcohol Syndrome. While interference with NMDA and GABAA neurotransmission during synaptogenesis is putatively responsible for much of ethanol's neurotoxic action, other mechanisms may also be operative in that ethanol kills some populations of neurons that are not affected by NMDA antagonist or GABAmimetic drugs. The applicants have recently discovered that an ethanol-like neurodegenerative syndrome can be induced in the developing rodent brain by certain solvents that are widely used in the industrial world to facilitate the manufacturing process or to dissolve and/or add functionality to marketed products, including injectable drugs used in human medicine. For example, we have found that dimethyl sulfoxide (DMSO) and propylene glycol, which are widely used throughout the world and are generally considered having a very low toxicity potential, trigger a robust neurodegenerative reaction in the developing rodent brain. This is not a property of all solvents in that polyethylene glycol, a very widely used solvent, does not display such activity. The Aims of the proposed research are to more fully characterize the neurodegenerative reactions induced by DMSO and propylene glycol, to screen other solvents for their ability to mimic this type of neurodegenerative phenomenon, to evaluate the degree of risk associated with using these agents as solvent vehicles for drugs administered intravenously to human neonates and, by a combined in vivo/in vitro approach, attempt to elucidate mechanisms underlying these newly discovered neurotoxic phenomena.

描述（由申请人提供）：这是先前提交的申请（R01-ES012443-01）的第二次修订。最近的研究表明，几类药物中的任何一种都可以在体内发育的啮齿动物中枢神经系统中引发细胞凋亡性神经变性，这些药物具有异常抑制神经元活动的共同特性。脆弱期与突触发生期一致，也称为大脑生长突增期，该期发生在啮齿类动物出生后（出生后前两周）以及人类产前和出生后（妊娠晚期和出生后几年）。违规药物包括阻断 NMDA 谷氨酸受体的药物、过度激活 GABAA 受体的药物以及同时具有 NMDA 拮抗剂和 GABA 模拟特性的乙醇。乙醇的凋亡作用是解释与人类胎儿酒精综合症相关的脑质量减少和神经行为紊乱的一个有希望的候选者。虽然突触发生过程中对 NMDA 和 GABAA 神经传递的干扰被认为是乙醇大部分神经毒性作用的原因，但其他机制也可能起作用，因为乙醇会杀死一些不受 NMDA 拮抗剂或 GABA 模拟药物影响的神经元群。申请人最近发现，工业界广泛使用的某些溶剂可以在发育中的啮齿动物大脑中诱发类似乙醇的神经退行性综合症，这些溶剂可以促进制造过程或溶解市售产品和/或向市售产品添加功能，包括注射剂用于人类医学的药物。例如，我们发现二甲亚砜（DMSO）和丙二醇在世界各地广泛使用，通常被认为具有非常低的毒性潜力，会在发育中的啮齿动物大脑中引发强烈的神经退行性反应。这并不是所有溶剂都具有的特性，因为聚乙二醇这种使用非常广泛的溶剂并不表现出这种活性。拟议研究的目的是更全面地表征 DMSO 和丙二醇引起的神经退行性反应，筛选其他溶剂模拟此类神经退行性现象的能力，评估与使用这些试剂作为溶剂载体相关的风险程度为人类新生儿静脉注射药物，并通过体内/体外相结合的方法，试图阐明这些新发现的神经毒性现象的机制。