Neurodevelopmental Apoptosis

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，在体内发育的啮齿动物中枢神经系统中，细胞凋亡性神经退行性变性可以由几种具有异常抑制神经元活动的共同特性的药物中的任何一类触发。易受伤害的时期与突触发生相一致，也被称为大脑生长突增期，发生在啮齿动物出生后（出生后的前两周），发生在人类出生前和出生后（妊娠晚期和出生后几年）。其中包括阻断NMDA谷氨酸受体的药物、过度激活GABAA受体的药物和同时具有NMDA拮抗剂和GABAA类药物特性的乙醇。乙醇的细胞凋亡作用是解释与人类胎儿酒精综合征相关的脑质量减少和神经行为障碍的一个有希望的候选人。虽然在突触发生过程中对NMDA和GABAA神经传递的干扰被认为是乙醇神经毒性作用的主要原因，但其他机制也可能起作用，即乙醇杀死一些不受NMDA拮抗剂或GABAA类药物影响的神经元群。申请人最近发现，某些溶剂可以在发育中的啮齿动物大脑中诱导乙醇样神经退行性综合征，这些溶剂广泛用于工业世界，以促进生产过程或溶解和/或增加市场产品的功能，包括人类医学中使用的注射药物。例如，我们发现二甲基亚砜（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，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，聚乙二醇，一种非常广泛使用的溶剂，没有表现出这种活性。拟议研究的目的是更全面地表征DMSO和丙二醇诱导的神经退行性反应，筛选其他溶剂模拟这种神经退行性现象的能力，评估使用这些试剂作为静脉注射给人新生儿药物的溶剂载体的风险程度，并通过体内/体外联合方法，试图阐明这些新发现的神经毒性现象背后的机制。

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.