Propylene Glycol after TBI: Biomarker of Altered Brain Metabolism

描述(由申请人提供)：我们最近证明，在人类创伤性脑损伤后，脑脊液(环绕大脑的一种透明液体)中丙二醇(PG)的浓度增加到高于通常预期的水平，因为它被用于在重症监护病房(ICU)输送药物。这一发现使我们认为PG是通过甲基乙二醛途径在大脑内产生的，这是一种替代葡萄糖(大脑燃料)的能量产生途径。众所周知，脑损伤后血糖升高(Vespa等人，2006年；Classen等人，2005年；Vespa等人，2002年)。然而，据我们所知，很少有研究涉及创伤后大脑中PG的存在。因此，研究这些途径对于开发治疗脑创伤的“代谢疗法”至关重要。鉴于目前缺乏关于脑损伤能量产生的文献来完整地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产生的程度是至关重要的。由于PG在损伤后的高丰度，以及其在干扰大脑能量产生方面的潜在潜力，PG可能显著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能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关联来证实丙二醇实际上是作为甲基乙二醛途径的副产品产生的。这些研究将指导未来的尝试，通过使用C13示踪剂研究来寻找PG形成的确切途径以及参与这一途径的所有其他化合物。此外，我们计划构建损伤后第一周人脑PG水平的时间表，以指导未来旨在抵消其产生和分解的努力。与公共健康相关：只有极少数(如果有的话)的研究涉及创伤后大脑中丙二醇的存在。因此，研究这些途径对于开发治疗脑创伤的“代谢疗法”至关重要。尤其是因为PG的存在已被证明是有害的替代葡萄糖途径的稳定最终产物。“新陈代谢疗法”的概念与公众健康密切相关，因为在美国，脑损伤是导致死亡和发病的主要原因，目前尚无治愈方法。

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.