Siesjö B K, Katsura K I, Kristián T, Li P A, Siesjö P
Laboratory for Experimental Brain Research, University of Lund, Sweden.
Acta Neurochir Suppl. 1996;66:8-14. doi: 10.1007/978-3-7091-9465-2_2.
The present article is concerned with mechanisms which are responsible for the exaggerated brain damage observed in hyperglycemic animals subjected to transient global or forebrain ischemia. Since hyperglycemia enchances the production of lactate plus H+ during ischemia, it seems likely that aggravation of damage is due to exaggerated intra- and extracellular acidosis. This contention is supported by results showing a detrimental effect of extreme hypercapnia in normoglycemic rats subjected to transient ischemia or to hypoglycemic coma. Enhanced acidosis may exaggerate ischemic damage by one of three mechanisms: (i) accelerating free radical production via H(+)-dependent reactions, some of which are catalyzed by iron released from protein bindings by a lowering of pH, (ii) by perturbing the intracellular signal transduction pathway, leading to changes in gene expression or protein synthesis, or (iii) by activating endonucleases which cause DNA fragmentation. While activation of endonucleases must affect the nucleus, the targets of free radical attack are not known. Microvessels are considered likely targets of such attack in sustained ischemia and in trauma; however, enhanced acidosis is not known to aggravate microvascular dysfunction, or to induce inflammatory responses at the endothelial-blood interface. A more likely target is the mitochondrion. Thus, if the ischemia is of long duration (30 min) hyperglycemia triggers rapidly developing mitochondrial failure. It is speculated that this is because free radicals damage components of the respiratory chain, leading to a secondary deterioration of oxidative phosphorylation.
本文关注的是在经历短暂性全脑或前脑缺血的高血糖动物中观察到的脑损伤加剧的机制。由于高血糖会在缺血期间增强乳酸和H⁺的产生，损伤加剧似乎是由于细胞内和细胞外酸中毒加剧所致。这一观点得到了以下结果的支持：在经历短暂性缺血或低血糖昏迷的正常血糖大鼠中，极度高碳酸血症具有有害作用。增强的酸中毒可能通过以下三种机制之一加剧缺血性损伤：（i）通过H⁺依赖性反应加速自由基产生，其中一些反应由pH降低从蛋白质结合中释放的铁催化；（ii）扰乱细胞内信号转导途径，导致基因表达或蛋白质合成发生变化；或（iii）激活导致DNA片段化的核酸内切酶。虽然核酸内切酶的激活必定会影响细胞核，但自由基攻击的靶点尚不清楚。在持续性缺血和创伤中，微血管被认为是此类攻击的可能靶点；然而，尚不清楚增强的酸中毒是否会加剧微血管功能障碍，或在内皮-血液界面诱导炎症反应。更可能的靶点是线粒体。因此，如果缺血持续时间较长（30分钟），高血糖会引发迅速发展的线粒体功能衰竭。据推测，这是因为自由基损伤了呼吸链的成分，导致氧化磷酸化的继发性恶化。
