Hertz Leif
College of Basic Medical Sciences, China Medical University, Shenyang, PR China.
Neuropharmacology. 2008 Sep;55(3):289-309. doi: 10.1016/j.neuropharm.2008.05.023. Epub 2008 Jun 3.
In cerebral ischemia survival of neurons, astrocytes, oligodendrocytes and endothelial cells is threatened during energy deprivation and/or following re-supply of oxygen and glucose. After a brief summary of characteristics of different cells types, emphasizing the dependence of all on oxidative metabolism, the bioenergetics of focal and global ischemia is discussed, distinguishing between events during energy deprivation and subsequent recovery attempt after re-circulation. Gray and white matter ischemia are described separately, and distinctions are made between mature and immature brains. Next comes a description of bioenergetics in individual cell types in culture during oxygen/glucose deprivation or exposure to metabolic inhibitors and following re-establishment of normal aerated conditions. Due to their expression of NMDA and non-NMDA receptors neurons and oligodendrocytes are exquisitely sensitive to excitotoxicity by glutamate, which reaches high extracellular concentrations in ischemic brain for several reasons, including failing astrocytic uptake. Excitotoxicity kills brain cells by energetic exhaustion (due to Na(+) extrusion after channel-mediated entry) combined with mitochondrial Ca(2+)-mediated injury and formation of reactive oxygen species. Many (but not all) astrocytes survive energy deprivation for extended periods, but after return to aerated conditions they are vulnerable to mitochondrial damage by cytoplasmic/mitochondrial Ca(2+) overload and to NAD(+) deficiency. Ca(2+) overload is established by reversal of Na(+)/Ca(2+) exchangers following Na(+) accumulation during Na(+)-K(+)-Cl(-) cotransporter stimulation or pH regulation, compensating for excessive acid production. NAD(+) deficiency inhibits glycolysis and eventually oxidative metabolism, secondary to poly(ADP-ribose)polymerase (PARP) activity following DNA damage. Hyperglycemia can be beneficial for neurons but increases astrocytic death due to enhanced acidosis.
在脑缺血过程中，能量剥夺期间和/或重新供应氧气和葡萄糖后，神经元、星形胶质细胞、少突胶质细胞和内皮细胞的存活受到威胁。在简要总结不同细胞类型的特征后，强调了所有细胞对氧化代谢的依赖性，接着讨论了局灶性和全脑缺血的生物能量学，区分了能量剥夺期间的事件以及再灌注后随后的恢复尝试。分别描述了灰质和白质缺血情况，并区分了成熟脑和未成熟脑。接下来描述了在培养的单个细胞类型中，在氧/葡萄糖剥夺或暴露于代谢抑制剂期间以及恢复正常通气条件后的生物能量学。由于神经元和少突胶质细胞表达N-甲基-D-天冬氨酸（NMDA）和非NMDA受体，它们对谷氨酸介导的兴奋毒性极为敏感，由于多种原因，包括星形胶质细胞摄取功能障碍，缺血脑中谷氨酸细胞外浓度会升高。兴奋毒性通过能量耗竭（由于通道介导的进入后Na⁺外流）、线粒体Ca²⁺介导的损伤和活性氧的形成杀死脑细胞。许多（但不是所有）星形胶质细胞在能量剥夺期间能长时间存活，但恢复通气条件后，它们易受细胞质/线粒体Ca²⁺过载导致的线粒体损伤以及NAD⁺缺乏的影响。在Na⁺-K⁺-Cl⁻共转运体刺激或pH调节期间Na⁺积累后，Na⁺/Ca²⁺交换体逆转导致Ca²⁺过载，以补偿过量的酸产生。DNA损伤后聚（ADP-核糖）聚合酶（PARP）活性导致NAD⁺缺乏，继而抑制糖酵解并最终抑制氧化代谢。高血糖对神经元可能有益，但由于酸中毒加剧会增加星形胶质细胞死亡。
