Propylene Glycol after TBI: Biomarker of Altered Brain Metabolism

描述（由申请人提供）：我们最近已经证明，在人创伤性脑损伤后，脑脊液（一种围绕大脑的透明液体）中的丙二醇（PG）浓度增加至高于其在重症监护室（ICU）中用于递送药物的正常预期浓度。这一发现使我们认为PG是通过甲基乙二醛途径在大脑中产生的，这是一种替代的葡萄糖（大脑燃料）能量产生途径。已经充分证实，脑损伤后血糖升高（Vespa等人，2006; Classen等人，2005; Vespa等人，2002年）。然而，据我们所知，很少有研究（如果有的话）涉及创伤后大脑中PG的存在。因此，研究这些途径对脑创伤的“代谢疗法”的发展至关重要。鉴于目前缺乏关于脑损伤能量产生的文献来完全解释这些代谢变化背后的机制，我们认为研究替代葡萄糖能量产生途径和PG产生的程度至关重要。由于其在损伤后的高丰度及其在中断大脑中能量产生的潜在效力，PG可能会显着改变目前流行的损伤后能量产生模式。特别是因为PG可能是回答为什么大脑在受伤后不产生能量的问题的关键，尽管有燃料可用。因此，我们打算通过建立这些化合物之间的相关性来确认丙二醇实际上是丙酮醛途径的副产物。这些研究将指导未来的尝试，以找到确切的途径参与形成的PG以及所有其他化合物参与这一途径，通过使用C13示踪剂的研究。此外，我们计划构建一个时间轴的PG水平在人类大脑受伤后的第一个星期，以指导未来的努力，旨在抵消其生产和分解。公共卫生相关性：只有很少的研究（如果有的话）讨论了创伤后丙二醇在大脑中的存在。因此，研究这些途径对脑创伤的“代谢疗法”的发展至关重要。特别是，因为PG的存在已被证明是有害的替代葡萄糖途径的稳定终产物。“代谢疗法”的概念与公共卫生有着巨大的相关性，因为脑损伤无法治愈，而脑损伤是美国死亡率和发病率的主要原因。

DESCRIPTION (provided by applicant): We have recently demonstrated that propylene glycol (PG) concentrations in cerebrospinal fluid (a clear fluid that surrounds the brain) increase following human traumatic brain injury to above what would normally be expected given its use in delivering drugs in the intensive care unit (ICU). This finding led us to think that PG is produced within the brain via the methylglyoxal pathway, an alternate glucose (brain fuel) energy production pathway. It has been well established that blood glucose are elevated following brain injury (Vespa et al., 2006; Classen et al., 2005; Vespa et al., 2002). However, to our knowledge few, if any, studies have addressed the presence of PG in the brain following trauma. As a result, it is crucial to the development of a `metabolic therapy' for brain trauma to investigate these pathways. Given the lack of the currently available literature on brain injury energy production to completely explain the mechanisms behind these metabolic changes, we believe it is of utmost importance to investigate the extent of alternate glucose energy production pathways and PG production. Due to its high abundance following injury and its potential potency in interrupting energy production in the brain, PG might significantly alter the currently prevailing post-injury energy production paradigm. Especially since PG might be the key to answer the question of why the brain does not produce energy after injury despite fuel availability. Consequently, we intend to confirm that propylene glycol is in fact produced as a byproduct of the methylglyoxal pathway by establishing a correlation between these compounds. These studies will guide future attempts to find the exact pathway involved in the formation of PG as well as all other compounds involved in this pathway by using C13 tracer studies. Additionally, we plan to construct a timeline of PG levels in the human brain over the first week post-injury to guide future efforts intended to counteract its production and breakdown. PUBLIC HEALTH RELEVANCE: Only few, if any, studies have addressed the presence of propylene glycol in the brain following trauma. As a result, it is crucial to the development of a `metabolic therapy' for brain trauma to investigate these pathways. Particularly, because the presence of PG has been shown to be the stable end-product of a deleterious alternative glucose pathway. The concept of `metabolic therapy is of tremendous relevance to public health, since there is no cure for brain injury, a major cause of mortality and morbidity in the United States.