Cerebral Lactate Metabolism Following Human Traumatic Brain Injury

描述(由申请者提供)：本项目的重点是我们最近的证明，创伤性脑损伤(TBI)在最初的12-24小时后，通常伴随着显著的脑乳酸摄取和利用。这一发现不被当代创伤后脑代谢功能障碍的概念所涵盖，也不容易与乳酸积累和酸中毒是创伤后细胞死亡的常见原因的观点相一致。乳酸是理解创伤病理生物学的基础。此外，它正成为通过脑微透析进行神经监测的重要组成部分；在动-颈静脉测量和磁共振波谱中，它被认为是脑缺血的重要标志。鉴于乳酸在颅脑损伤后代谢功能障碍中的重要作用尚不完全清楚，我们建议研究其在脑内的摄取及其代谢。我们的主要假设是，在创伤性脑损伤后，乳酸在大脑中被摄取和氧化。我们还打算以类似和平行的方式研究大脑的葡萄糖代谢，以更全面地了解损伤引起的碳水化合物代谢的变化。为了回答这一项目中涉及的关键科学问题，我们计划采取一种新的方法，使用氢(D2)和碳(13C-)葡萄糖和乳酸同位素示踪代谢技术来研究脑损伤患者的脑代谢。我们的具体目标是：1.确定脑创伤后葡萄糖摄取、糖酵解和葡萄糖氧化受到影响(抑制)的程度。2.确定脑创伤后脑乳酸摄取和氧化受影响(增强)的程度。3.探讨血乳酸和葡萄糖氧化率与颅脑损伤后临床特征和预后的关系。如果该项目中提出的研究证实乳酸是受损大脑的一种可行的燃料，下一步将考虑将乳酸注射作为脑损伤的“代谢疗法”。我们之前已经证明，在创伤性脑损伤后，大脑会吸收一种名为乳酸的化学物质。这个项目将确定大脑是否正在使用乳酸来帮助它在受伤后恢复。如果该项目中提出的研究证实乳酸有助于受伤的大脑，下一步将考虑将乳酸管理作为治疗脑损伤的新的“代谢疗法”。

DESCRIPTION (provided by applicant): This project is focused on our recent demonstration that traumatic brain injury (TBI), after the first 12-24 hours, is typically accompanied by significant cerebral lactate uptake and utilization. This finding is not encompassed by contemporary concepts of post-traumatic cerebral metabolic dysfunction, and cannot easily be reconciled with the view that lactate accumulation and acidosis are common causes of cell death after trauma. Lactate is fundamental to the understanding of traumatic pathobiology. Furthermore, it is becoming a key component of neuro-monitoring through cerebral microdialysis; and it is regarded as an important marker of cerebral ischemia in arterio-jugular measurements, and MR spectroscopy. Because of the important yet incompletely understood role of lactate in metabolic dysfunction after TBI, we propose to study its uptake by the brain, and its metabolism. Our main hypothesis is that lactate is taken and oxidized in the brain after traumatic brain injury. We also intend to study cerebral glucose metabolism in an analogous and parallel fashion, to understand more completely the alterations in carbohydrate metabolism induced by injury. To answer the key scientific questions addressed in this project, we plan to take the novel approach of using deuterium (D2) and carbon (13C-)) glucose and lactate isotope tracer metabolic techniques to study cerebral metabolism in brain injury patients. Our specific aims are: 1. To determine the extent to which brain glucose uptake, glycolysis, and glucose oxidation are affected (suppressed) after TBI. 2. To determine the extent to which brain lactate uptake and oxidation are affected (augmented) after TBI. 3. To determine the extent to which the rates of lactate and glucose oxidation correlate with clinical characteristics and outcome after TBI. If the studies proposed in this project confirm that lactate is a viable fuel for the injured brain, the next step will be to consider lactate administration as "metabolic therapy" for brain injury. We have previously shown that the brain takes up the chemical called lactate after traumatic brain injury. This project will determine if the brain is using the lactate to help it recover after injury. If the studies proposed in this project confirm that lactate helps the injured brain, the next step will be to consider lactate administration as new "metabolic therapy" for brain injury.