Propylene glycol after human traumatic brain injury: Novel biomarker of altered glucose metabolism

Background: Traumatic brain injury (TBI) metabolism research has indicated that despite increased levels of glucose, conventional cerebral glucose metabolism rarely rises to the expected supra-normal levels to compensate for the injury-induced decrease in oxidative metabolism. In fact, it has been well established that increased plasma glucose (PlGluc) is detrimental following TBI. These observations suggest the activation of alternative glucose metabolic pathways. Investigations around a novel metabolite, propylene glycol (PG), a compound that we recently identitifed in cerebrospinal fluid (CSF) of TBI patients, suggested that increased PlGluc results in an increased rate of glycation. Glycation is a deleterious metabolic process resulting in the production of toxic PG, advanced glycation end products (AGEs), and methylglyoxal. Both, methylglyoxal and AGEs, have been shown to affect physiological aging, and neurodegenerative diseases, such as Alzheimer's. We hypothesize that the methylglyoxal pathway is likely to be activated following brain injury. As a result, glucose might be involved in unique pathophysiological mechanisms following TBI. Methods: Daily CSF samples of 34 consented TBI patients (38+/-12 years, GCS 6.5+/-2.1,76% male) and five consented normal pressure hydrocephalus (non-injured) patients were analyzed using proton-nuclear magnetic resonance (H-NMR) spectroscopy and gas chromatography/mass spectroscopy (GC/MS). Additionally, arterial blood samples were collected and analyzed for glucose concentrations using the GM-7 Analox Analyzer. Results: Statistical analysis of PlGluc levels and PG, an end-product of glycation, revealed a significant correlation (r=0.432; p=0.001). PlGluc higher than 160mg/dl resulted in significantly higher overall PG concentrations (PGGluc<160=1.35mM vs. PlGluc>160=4.38mM; p=0.004). Additionally, propylene glycol correlated significantly with CSF lactate concentrations (r=0.408; p=0.002), which was expected since PG can very easily be converted to lactate. Most interestingly, the GC/MS analysis of CSF revealed the presence of methylglyoxal. Methylglyoxal was significantly higher in the CSF of TBI patients when compared to the CSF of non-injured patients. On average, TBI patients had 56+/-14ng/g of sample of methylglyoxal present in their CSF, whereas the non-injured patients only had 9.4+/-8.0ng/g of sample (p=0.05). Conclusion: While there have been numerous studies on glucose metabolism following TBI, to our knowledge, no studies in TBI research have examined the methylglyoxal pathway. This process can be activated after glucose initiates glycation under conditions of hyperglycemia and the presence of free radicals. This pathway has been recently investigated in diabetes research. Considering the physiological similarities between hyperglycemia in diabetes and TBI with regards to the presence of free radicals and the increased susceptibility to developing neurodegenerative diseases, glycation may be an important pathophysiological mechanism following TBI. The detection of PG and methylglyoxal in the CSF of TBI patients suggests the presence of glycation reactions in the injured brain under conditions of high PlGluc. We speculate that free radicals inhibit glycolysis at the glyceraldehydes-3-phosphate (G3P) step. G3P then gets metabolized to methylglyoxal, AGEs, and PG, all of which can have detrimental effects on the injured brain. In light of these data, we believe that it is of utmost importance to monitor PlGluc and glycation marker levels closely in severely head injured patients to prevent further metabolic distress and cell damage.