Drug-Induced Apoptosis: Mechanism by which Alcohol and Many Other Drugs Can Disrupt Brain Development.
Drug-Induced Apoptosis: Mechanism by which Alcohol and Many Other Drugs Can Disrupt Brain Development.
复制标题
DOI：
10.3390/brainsci3031153
复制
发表时间：
2013-09-01
期刊：
影响因子：
3.3
通讯作者：
Olney JW
中科院分区：
文献类型：
--
作者：
Creeley CE;Olney JW
母亲在怀孕期间摄入酒精会导致一种称为胎儿酒精谱系障碍(FASD)的残疾综合征，这可能包括头面部畸形、大脑结构病理和各种长期的神经精神障碍。有令人信服的证据表明，在胚胎发育早期(怀孕第4周)暴露在酒精中会导致面部和大脑正常发育所必需的细胞群过度死亡。虽然这可以解释有时伴随FASD的颅面畸形和某些结构性脑异常，但在许多情况下，这些特征缺失，FASD综合征主要表现为神经行为障碍。从文献中还不清楚酒精是如何导致这些后一种表现的。在这篇综述中，我们将描述越来越多的证据证明，在相当于人类妊娠晚期的一段时间内，酒精在动物(包括非人类灵长类动物)中给予酒精时，会引发发育中大脑中神经元和少突胶质细胞(OLs)的广泛凋亡死亡。这种细胞死亡反应与大脑的变化有关，包括整体或局部的脑质量减少，以及长期的神经行为障碍。我们还将审查证据表明，儿科和产科医学中使用的许多药物，包括全麻药(GAS)和抗癫痫药(AEDs)，模拟酒精在相当于晚期妊娠的动物大脑中引发广泛的神经元和OL的凋亡死亡，以及在婴儿早期暴露于GAS或在妊娠晚期暴露于AEDs，显著增加了FASD样神经行为障碍的发生率。这些发现提供了证据，表明在婴儿期早期将发育中的人脑暴露于气体中，或者在妊娠晚期暴露于酒精或AEDs中，可导致FASD样神经发育障碍综合征。我们认为，酒精、GAS和AEDs导致神经行为障碍综合征的机制是通过触发发育中大脑中神经元和OL(或其前体)的凋亡死亡和缺失。因此，有必要进行研究，以破译这些药物触发细胞凋亡的机制，最终目标是了解如何防止这些药物导致神经发育障碍。
Maternal ingestion of alcohol during pregnancy can cause a disability syndrome termed Fetal Alcohol Spectrum Disorder (FASD), which may include craniofacial malformations, structural pathology in the brain, and a variety of long-term neuropsychiatric disturbances. There is compelling evidence that exposure to alcohol during early embryogenesis (4th week of gestation) can cause excessive death of cell populations that are essential for normal development of the face and brain. While this can explain craniofacial malformations and certain structural brain anomalies that sometimes accompany FASD, in many cases these features are absent, and the FASD syndrome manifests primarily as neurobehavioral disorders. It is not clear from the literature how alcohol causes these latter manifestations. In this review we will describe a growing body of evidence documenting that alcohol triggers widespread apoptotic death of neurons and oligodendroglia (OLs) in the developing brain when administered to animals, including non-human primates, during a period equivalent to the human third trimester of gestation. This cell death reaction is associated with brain changes, including overall or regional reductions in brain mass, and long-term neurobehavioral disturbances. We will also review evidence that many drugs used in pediatric and obstetric medicine, including general anesthetics (GAs) and anti-epileptics (AEDs), mimic alcohol in triggering widespread apoptotic death of neurons and OLs in the third trimester-equivalent animal brain, and that human children exposed to GAs during early infancy, or to AEDs during the third trimester of gestation, have a significantly increased incidence of FASD-like neurobehavioral disturbances. These findings provide evidence that exposure of the developing human brain to GAs in early infancy, or to alcohol or AEDs in late gestation, can cause FASD-like neurodevelopmental disability syndromes. We propose that the mechanism by which alcohol, GAs and AEDs produce neurobehavioral deficit syndromes is by triggering apoptotic death and deletion of neurons and OLs (or their precursors) from the developing brain. Therefore, there is a need for research aimed at deciphering mechanisms by which these agents trip the apoptosis trigger, the ultimate goal being to learn how to prevent these agents from causing neurodevelopmental disabilities.