New insights and new issues in developmental neurotoxicology
New insights and new issues in developmental neurotoxicology
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DOI：
10.1016/s0161-813x(01)00092-4
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发表时间：
2002-12-01
期刊：
影响因子：
3.4
通讯作者：
Olney, JW
中科院分区：
文献类型：
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作者：
Olney, JW
在这里，我将回顾积累的证据，在突触发生的发育期，也被称为大脑生长突增期，神经元是非常敏感的特定干扰突触环境。在此期间，NMDA谷氨酸（Glu）受体活性的异常增加触发兴奋性神经变性，神经元活性的异常抑制（通过阻断NMDA Glu受体或过度激活GABA（A）受体）触发神经元自杀（细胞凋亡）。只有一个短暂的干扰，持续几个小时，是足以触发兴奋毒性或凋亡神经变性在这一发展时期。乙醇具有NMDA拮抗剂和GABA模拟物的特性，在发育中的大鼠、小鼠或豚鼠脑中引发广泛的凋亡性神经变性，这为与人类胎儿酒精综合征（FAS）相关的脑质量减少和终身神经行为障碍提供了可能的解释。不同物种的大脑在出生后的不同时间会出现生长突增。在大鼠和小鼠中，它是出生后的事件，但在人类中，它从妊娠的第6个月延伸到出生后的几年。因此，在胎儿和新生儿的发育中有一个持续数年的时期，在此期间，未成熟的中枢神经系统（CNS）神经元对环境因子（其具体数量和种类仍有待确定）非常敏感，这些环境因子可以通过诱导突触环境中的特定异常变化而引发广泛的神经变性。到目前为止，已确定的药物包括可能被孕妇滥用的药物（乙醇、苯环己哌啶（PCP）（天使尘）、氯胺酮（特殊K）、一氧化二氮（笑气）、巴比妥类药物、苯二氮卓类药物）和许多在产科和儿科医学中用作镇静剂、抗惊厥药或麻醉剂的药物（所有全身麻醉剂都是NMDA拮抗剂或GABA模拟物）。人类环境中的许多其他化学物质仍有待评估其导致发育中的CNS神经元自杀的能力，这为发育神经毒理学领域提供了令人兴奋的挑战。(C)2002年爱思唯尔科技有限公司All rights reserved.
Here, I will review accumulating evidence that during the developmental period of synaptogenesis, also known as the brain growth spurt period, neurons are very sensitive to specific disturbances in their synaptic environment. During this period abnormal increases in NMDA glutamate (Glu) receptor activity triggers excitotoxic neurodegeneration, and abnormal inhibition of neuronal activity (by blockade of NMDA Glu receptors or excessive activation of GABA(A) receptors) triggers neuronal suicide (apoptosis). Only a transient disturbance, lasting for a few hours, is sufficient to trigger either excitotoxic or apoptotic neurodegeneration during this developmental period. Ethanol, which has both NMDA antagonist and GABAmimetic properties, triggers widespread apoptotic neurodegeneration in the developing rat, mouse or guinea pig brain, and this provides a likely explanation for the reduced brain mass and lifelong neurobehavioral disturbances associated with the human fetal alcohol syndrome (FAS). The brain growth spurt occurs in different species at different times relative to birth. In rats and mice it is a postnatal event, but in humans it extends from the 6th month of gestation to several years after birth. Thus, there is a period in fetal and neonatal human development, lasting for several years, during which immature central nervous system (CNS) neurons are exquisitely sensitive to environmental agents (the specific number and variety of which remains to be established) that can trigger widespread neurodegeneration by inducing specific abnormal changes in the synaptic environment. Agents identified thus far include drugs that may be abused by pregnant mothers (ethanol, phencyclidine (PCP) (angel dust), ketamine (Special K), nitrous oxide (laughing gas), barbiturates, benzodiazepines) and many medicinals used in obstetric and pediatric medicine as sedatives, anti-convulsants or anesthetics (all general anesthetics are either NMDA antagonists or GABAmimetics). Many other chemicals in the human environment remain to be evaluated for their ability to cause developing CNS neurons to commit suicide, and this provides an exciting challenge for the field of developmental neurotoxicology. (C) 2002 Elsevier Science Inc. All rights reserved.