Berger Richard, Garnier Yves, Jensen Arne
Department of Obstetrics and Gynecology, University of Bochum, Bochum, Germany.
J Soc Gynecol Investig. 2002 Nov-Dec;9(6):319-28.
Children who suffer from perinatal brain injury often deal with the dramatic consequences of this misfortune for the rest of their lives. Despite the severe clinical and socioeconomic significance, no effective clinical strategies have yet been developed to counteract this condition. As shown in recent studies, perinatal brain injury is usually brought about by cerebral ischemia, cerebral hemorrhage, or an ascending intrauterine infection. This review focuses on the pathophysiologic pathways activated by these insults and describes neuroprotective strategies that can be derived from these mechanisms. Fetal cerebral ischemia causes an acute breakdown of neuronal membrane potential followed by the release of excitatory amino acids such as glutamate and aspartate. Glutamate binds to postsynaptically located glutamate receptors that regulate calcium channels. The resulting calcium influx activates proteases, lipases, and endonucleases, which in turn destroy the cellular skeleton. A second wave of neuronal cell damage occurs during the reperfusion phase. This cell damage is thought to be caused by the postischemic release of oxygen radicals, synthesis of nitric oxide, inflammatory reactions, and an imbalance between the excitatory and inhibitory neurotransmitter systems. Furthermore, secondary neuronal cell damage may be brought about in part by induction of a cellular suicide program known as apoptosis. Recent studies have shown that inflammatory reactions not only aggravate secondary neuronal damage after cerebral ischemia, but may also injure the immature brain directly. This damage may be mediated by cardiovascular effects of endotoxins leading to cerebral hypoperfusion and by activation of apoptotic pathways in oligodendrocyte progenitors through the release of proinflammatory cytokines. Periventricular or intraventricular hemorrhage (PIVH) is a typical lesion of the immature brain. The inability of preterm fetuses to redistribute cardiac output in favor of the central organs and their lack of cerebral autoregulation may cause significant fluctuations in cerebral blood flow when oxygen is in short supply. Disruption of the thin-walled blood vessels in the germinal matrix with subsequent cerebral hemorrhage is often the inevitable result and is at times associated with cerebral hemorrhagic infarction. Knowledge of these pathophysiologic mechanisms has enabled scientists to develop new therapeutic strategies, which have been shown to be neuroprotective in animal experiments. The potential of such therapies is discussed here, particularly the promising effects of postischemic induction of cerebral hypothermia, the application of the calcium-antagonist flunarizine, and the administration of magnesium.
患有围产期脑损伤的儿童往往要在余生应对这场不幸带来的巨大后果。尽管其具有严重的临床和社会经济意义，但尚未开发出有效的临床策略来对抗这种情况。如最近的研究所示，围产期脑损伤通常由脑缺血、脑出血或上行性宫内感染引起。本综述重点关注这些损伤激活的病理生理途径，并描述可从这些机制中推导出来的神经保护策略。胎儿脑缺血会导致神经元膜电位急性崩溃，随后释放谷氨酸和天冬氨酸等兴奋性氨基酸。谷氨酸与位于突触后调节钙通道的谷氨酸受体结合。由此产生的钙内流激活蛋白酶、脂肪酶和核酸酶，进而破坏细胞骨架。在再灌注阶段会发生第二轮神经元细胞损伤。这种细胞损伤被认为是由缺血后氧自由基的释放、一氧化氮的合成、炎症反应以及兴奋性和抑制性神经递质系统之间的失衡引起的。此外，继发性神经元细胞损伤可能部分是由一种称为凋亡的细胞自杀程序的诱导所导致。最近的研究表明，炎症反应不仅会加重脑缺血后的继发性神经元损伤，还可能直接损伤未成熟脑。这种损伤可能由内毒素的心血管效应导致脑灌注不足以及通过促炎细胞因子的释放激活少突胶质细胞前体细胞中的凋亡途径介导。脑室周围或脑室内出血（PIVH）是未成熟脑的典型病变。早产胎儿无法将心输出量重新分配以利于中央器官，且缺乏脑自动调节功能，这可能导致在氧气供应不足时脑血流量出现显著波动。生发基质中薄壁血管破裂并随后发生脑出血往往是不可避免的结果，有时还会伴有脑出血性梗死。对这些病理生理机制的了解使科学家能够开发新的治疗策略，这些策略在动物实验中已被证明具有神经保护作用。这里讨论了此类疗法的潜力，特别是缺血后诱导脑低温、应用钙拮抗剂氟桂利嗪以及给予镁的显著效果。
