Acute Brain Injury, Mechanisms and Consequences

这是一份申请，要求竞争性续领已获资助3年的RO 1补助金（11/1/98 - 2001年10月31日），以支持旨在阐明兴奋性毒性和/或凋亡细胞死亡机制作用的研究 在与头部创伤和缺氧/缺血相关的发育（围产期）脑损伤中。除了 在赠款期间解决这些目标，PI意外发现， 发育的突触发生期短暂的酒精中毒引发了大量的凋亡 神经变性，从发育中的大鼠、小鼠或哺乳动物的许多不同区域删除数百万个神经元。 豚鼠大脑我们的研究结果表明，乙醇通过双重机制触发细胞凋亡-阻断细胞凋亡。 NMDA谷氨酸受体和GABAA受体的过度激活。我们认为，我们的发现可以 这有助于解释人类胎儿大脑质量的减少和终生的神经行为障碍 酒精综合征（FAS）。这一发现的重要性被随之而来的证据扩大了，即乙醇 神经毒性特性被许多其他药剂所共有，这些药剂或者阻断NMDA谷氨酸受体， 激活GABA受体，并且这些药剂中的许多是滥用的药物和/或经常用于产科和哺乳动物。 儿科医学我们发现的一个重要特征是，在突触发生期（前2周）， 大鼠和小鼠在出生后，但人类在妊娠晚期和出生后的头几年）不同的神经元 不同人群对这些药物诱导骨质疏松症的反应具有不同的时间模式。 因此，根据暴露的时间，神经元组的不同组合将被删除， 这表明这是一种神经发育机制，可以导致广泛的神经精神疾病， 干扰.与这一解释相一致的是，有证据表明，FAS的受害者不仅表现出童年 多动/注意力缺陷和学习障碍，但成人精神病发病率高 精神障碍，包括重度抑郁症和精神病。这一竞争性更新提案的目的 有三个方面，第一个是继续探索兴奋毒性和凋亡机制在缺血性脑损伤中的作用。 第二和第三是更全面地表征分子、神经病理和 我们发现，凋亡性神经退行性综合征的神经行为方面可以在 通过在突触发生期间短暂暴露于乙醇来发育小鼠大脑。

This is an application for competing renewal of an RO1 grant which was funded for 3 years (11/1/98 - 10/31/01) to support studies aimed at clarfying the role(s) of excitotoxic and/or apoptotic cell death mechanisms in developmental (perinatal) brain injury associated with head trauma and hypoxia/ischemia. In addition to addressing these aims during the grant period, the PI has made the unanticipated discovery that during the synaptogenesis period of development transient ethanol intoxication triggers a massive wave of apoptotic neurodegeneration, deleting millions of neurons from many different regions of the developing rat, mouse or guinea pig brain. Our findings document that ethanol triggers apoptosis by a dual mechanism - blockade of NMDA glutamate receptors and excessive activation of GABAA receptors. We propose that our findings can help explain the reduced brain mass and lifelong neurobehavioral disturbances associated with the human fetal alcohol syndrome (FAS). Significance of this discovery is broadened by accompanying evidence that ethanol's neurotoxic properties are shared by numerous other agents that either block NMDA glutamate receptors or activate GABA^ receptors, and many of these agents are drugs of abuse and/or are used regularly in obstetric and pediatric medicine. An important feature of our findings is that within the synaptogenesis period (first 2 weeks after birth for rats and mice, but third trimester and first several years after birth for humans) different neuronal populations have different temporal patterns for responding to the apoptosis-inducing effects of these drugs. Thus, depending on the timing of exposure, different combinations of neuronal groups will be deleted, which signifies that this is a neurodevelopmental mechanism that can contribute to a wide spectrum of neuropsychiatric disturbances. Consistent with this interpretation is evidence that victims of FAS manifest not only childhood hyperactivity/attention deficit and learning disorders, but have a high incidence of adult onset psychiatric disturbances, including major depressive disorder and psychosis. The aims of this competing renewal proposal are threefold, the first being to continue exploring the role of excitotoxic and apoptotic mechanisms in ischemic neurodegeneration, and the second and third being to more fully characterize molecular, neuropathological and neurobehavioral aspects of the apoptotic neurodegenerative syndrome we have found can be induced in the developing mouse brain by transient exposure to ethanol during synaptogenesis.