Glycolysis and the significance of lactate in traumatic brain injury.
Glycolysis and the significance of lactate in traumatic brain injury.
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DOI：
10.3389/fnins.2015.00112
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发表时间：
2015
影响因子：
4.3
通讯作者：
Hutchinson PJ
中科院分区：
文献类型：
--
作者：
Carpenter KL;Jalloh I;Hutchinson PJ
在创伤性脑损伤（TBI）患者中，脑细胞外乳酸浓度和乳酸/丙酮酸比值的升高是公认的，并且在统计学上与不利的临床结果相关。脑细胞外乳酸通常被认为是葡萄糖的废物，葡萄糖通过糖酵解（embden - meyerhoff - parnas途径）代谢为丙酮酸，随后通过乳酸脱氢酶的作用转化为乳酸，并将乳酸出口到细胞外液中。在TBI中，糖酵解乳酸被归因于缺氧或线粒体功能障碍，尽管后者的确切性质尚不完全清楚。似乎与乳酸与不利结果的关联相反，越来越多的证据表明乳酸是有益的。大脑可以通过向神经元的三羧酸（TCA）循环供血来利用乳酸的观点在20年前首次发表，被称为星形细胞-神经元乳酸穿梭假说。乳酸脑利用的直接证据是5年前在TBI患者的脑微透析研究中首次获得的，该研究通过微透析导管给予13C标记的乳酸，同时收集新出现的微透析物，通过13C NMR分析，显示谷氨酰胺中的13C标记与TCA循环中的乳酸利用一致。这表明，当神经元受损严重，无法利用星形胶质细胞产生的葡萄糖乳酸时，即神经元和神经胶质代谢的解耦，高水平的细胞外乳酸会积累，这解释了高乳酸与不良预后之间的关联。最近，一项在TBI患者中静脉补充外源性乳酸的研究显示了通过替代终点判断有益效果的证据。在这里，我们回顾了目前关于脑外伤中糖酵解和乳酸的知识现状，如何在患者中测量，以及是否可以调节它以获得更好的临床结果。
In traumatic brain injury (TBI) patients, elevation of the brain extracellular lactate concentration and the lactate/pyruvate ratio are well-recognized, and are associated statistically with unfavorable clinical outcome. Brain extracellular lactate was conventionally regarded as a waste product of glucose, when glucose is metabolized via glycolysis (Embden-Meyerhof-Parnas pathway) to pyruvate, followed by conversion to lactate by the action of lactate dehydrogenase, and export of lactate into the extracellular fluid. In TBI, glycolytic lactate is ascribed to hypoxia or mitochondrial dysfunction, although the precise nature of the latter is incompletely understood. Seemingly in contrast to lactate's association with unfavorable outcome is a growing body of evidence that lactate can be beneficial. The idea that the brain can utilize lactate by feeding into the tricarboxylic acid (TCA) cycle of neurons, first published two decades ago, has become known as the astrocyte-neuron lactate shuttle hypothesis. Direct evidence of brain utilization of lactate was first obtained 5 years ago in a cerebral microdialysis study in TBI patients, where administration of 13C-labeled lactate via the microdialysis catheter and simultaneous collection of the emerging microdialysates, with 13C NMR analysis, revealed 13C labeling in glutamine consistent with lactate utilization via the TCA cycle. This suggests that where neurons are too damaged to utilize the lactate produced from glucose by astrocytes, i.e., uncoupling of neuronal and glial metabolism, high extracellular levels of lactate would accumulate, explaining the association between high lactate and poor outcome. Recently, an intravenous exogenous lactate supplementation study in TBI patients revealed evidence for a beneficial effect judged by surrogate endpoints. Here we review the current state of knowledge about glycolysis and lactate in TBI, how it can be measured in patients, and whether it can be modulated to achieve better clinical outcome.
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