Neurodevelopmental Apoptosis

神经发育细胞凋亡

• 批准号: 7239642
• 负责人: NURI B FARBER
• 金额: $ 34.45万
• 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 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7239642
• 关键词: Adolescence; Adult; Adverse effects; Affect; Age; Apoptosis; Apoptotic; Barbiturates; Benzodiazepines; Birth; Brain; Brain Mass; Brain region; Cerebral cortex; Cholinergic Agents; Class; Complex; Data; Development; Dimethyl Sulfoxide; Disinhibition; Dose; Drug Receptors; Drug usage; Drug vehicle; Emulsifying Agents; Encephalopathies; Ethanol; Fetal Alcohol Syndrome; Glutamate Receptor; Glutamates; Growth; Human; In Vitro; Injectable; Injury; Marketing; Medical; Medicine; Mus; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Nature; Nerve Degeneration; Neurons; Numbers; Pathway interactions; Pattern; Pediatric Neurology; Pharmaceutical Preparations; Phenobarbital; Phenytoin; Polyethylene Glycols; Population; Preclinical Drug Evaluation; Process; Property; Propylene Glycols; Propylene glycol; Rattus; Reaction; Research; Risk; Rodent; Solvents; Syndrome; Third Pregnancy Trimester; Toxic effect; Week; accomplished suicide; barbituric acid salt; biological research; cholinergic; gamma-Aminobutyric Acid; in vivo; inhibitory neuron; killings; manufacturing process; neonate; neurobehavioral; neurotoxic; neurotoxicity; neurotransmission; receptor; response; 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。最近已经表明，在体内发育中的任何类别中的任何类别的药物中，都可以触发凋亡的神经变性，这些药物具有共同的特性，具有异常抑制神经元活性的特性。脆弱性的时期与突触发生相吻合，也称为脑生长时期，这是在产后发生在啮齿动物（出生后的前2周），以及在人类（三个月和出生后几年）的产前和产后发生的。在违规药物中包括阻断NMDA谷氨酸受体的药物，使GABAA受体过度活化的药物和乙醇具有NMDA拮抗剂和Gabamimetic特性。乙醇的凋亡作用是解释与人类胎儿酒精综合征相关的脑质量和神经行为疾病减少的有前途的候选人。尽管突触发生过程中对NMDA和GABAA神经传递的干扰是乙醇的大部分神经毒性作用的造成的，但其他机制也可能是可行的，因为乙醇会杀死一些不受NMDA拮抗剂或Gabamimetic药物影响的神经元群体。申请人最近发现，可以在开发的啮齿动物大脑中引起类似乙醇的神经退行性综合征，这些溶剂在工业世界中广泛用于促进制造过程或溶解和/或溶解和/或添加功能性，包括在人类医学中使用的可注入药物。例如，我们发现二甲基亚硫氧化二甲基硫酸（DMSO）和丙二醇在世界范围内广泛使用，通常被认为具有非常低的毒性潜力，引发了发育中的啮齿动物大脑中强大的神经退行性反应。这并不是所有溶剂的特性，因为聚乙烯乙二醇（一种非常广泛使用的溶剂）并未显示出这种活性。 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阐明这些新发现的神经毒性现象的基础机制。