Metabolic Crisis After Traumatic Brain Injury is Associated with a Novel Microdialysis Proteome

Abstract

Background To examine if the metabolic distress after traumatic brain injury (TBI) is associated with a unique proteome. Methods Patients with severe TBI prospectively underwent cerebral microdialysis for the initial 96 h after injury. Hourly sampling of metabolism was performed and patients were categorized as having normal or abnormal metabolism as evidenced by the lactate/pyruvate ratio (LPR) threshold of 40. The microdialysate was frozen for proteomic batch processing retrospectively. We employed two different routes of proteomic techniques utilizing mass spectrometry (MS) and categorized as diagnostic and biomarker identification approaches. The diagnostic approach was aimed at finding a signature of MS peaks which can differentiate these two groups. We did this by enriching for intact peptides followed by MALDI-MS analysis. For the biomarker identification approach, we applied classical bottom-up (trypsin digestion followed by LC-MS/MS) proteomic methodologies. Results Five patients were studied, 3 of whom had abnormal metabolism and 2 who had normal metabolism. By comparison, the abnormal group had higher LPR (1609 ± 3691 vs. 15.5 ± 6.8, P < 0.001), higher glutamate (157 ± 84 vs. 1.8 ± 1.4 μM, P < 0.001), and lower glucose (0.27 ± 0.35 vs. 1.8 ± 1.1 mmol/l, P < 0.001). The abnormal group demonstrated 13 unique proteins as compared with the normal group in the microdialysate. These proteins consisted of cytoarchitectural proteins, as well as blood breakdown proteins, and a few mitochondrial proteins. A unique as yet to be characterized peptide was found at m/z (mass/charge) 4733.5, which may represent a novel biomarker of metabolic distress. Conclusion Metabolic distress after TBI is associated with a differential proteome that indicates cellular destruction during the acute phase of illness. This suggests that metabolic distress has immediate cellular consequences after TBI.

Dietary fructose aggravates the pathobiology of traumatic brain injury by influencing energy homeostasis and plasticity

“…It is well understood that TBI reduces the capacity of brain cells to metabolize energy. 7,8 Our current data show that TBI affects the BDNF system while fructose interferes with signaling of both insulin receptor and BDNF receptor (dashed lines). Therefore, fructose may present an additional challenge to cellular energy metabolism and TBI outcome.…”

Hemorrhagic Progression of a Contusion after Traumatic Brain Injury: A Review

“…The term ''progressive hemorrhagic injury'' has been used to refer to progression of an epidural hematoma, subdural hematoma, intraparenchymal contusion or hematoma, or subarachnoid hemorrhage (Oertel et al, 2002). Such broad usages are Lenzlinger et al, 2002;Morganti-Kossmann et al, 2002;Otto et al, 2002;Yatsiv et al, 2002;Lu et al, 2011;Hong et al, 2010 Excitotoxicity Yi andMetabolic derangements De et al, 2011Lakshmanan et al, 2010;Scafidi et al, 2009;Marcoux et al, 2008;Vespa et al, 2005 Apoptosis/necrosis/ autophagy Shojo et al, 2010;Nakajima et al, 2010;Hoh et al, 2010;Yamashima and Oikawa, 2009;Itoh et al, 2010;Robertson et al, 2009;Luo et al, 2010;Luo et al, 2011;Liao et al, 2009Ischemia Aoyama et al, 2008Stiefel et al, 2005;Engel et al, 2005;Mendez et al, 2004;Buczek et al, 2002;Oertel et al, 2005 imprecise, and the molecular mechanisms responsible for progression in each case is likely to be different. To avoid ambiguity, here we adopt the term ''hemorrhagic progression of a contusion'' (HPC).…”

Human Serum Metabolites Associate With Severity and Patient Outcomes in Traumatic Brain Injury

“…TBI is associated with a complex metabolic disruption that results in energy crisis and energy failure, which is the consequence of multiple mechanisms, including classical ischaemia (Coles et al, 2004), diffusion hypoxia (Menon et al, 2004), mitochondrial dysfunction (Lakshmanan et al, 2010) and increased energy needs (from excitotoxicity, seizure activity and spreading depolarization) (Timofeev et al, 2011). Thus far, the only approaches to examine this metabolic dysregulation have involved the use of cerebrospinal fluid (CSF), brain microdialysis, arteriojugular venous differences, or advanced metabolic imaging with positron emission tomography (PET) or magnetic resonance imaging and spectroscopy (MRIS), none of which are universally available, and are particularly problematic in less severe TBI.…”