An NMR Metabolomic Investigation of Early Metabolic Disturbances Following Traumatic Brain Injury in a Mammalian Model

The effects of traumatic brain injury (TBI) on brain chemistry and metabolism were examined in three groups of rats using high-resolution (1)H NMR metabolomics of brain tissue extracts and plasma. Brain injury in the TBI group (n = 6) was produced by lateral fluid percussion and regional changes in brain metabolites were analyzed at 1 h after injury in hippocampus, cortex and plasma and compared with changes in both a sham-surgery control group (n = 6) and an untreated control group (n = 6). Evidence was found of oxidative stress (e.g. decreases in ascorbate of 16.4% (p<0.01) and 29.7% (p<0.05) in cortex and hippocampus, respectively) in TBI rats versus the untreated control group, as well as excitotoxic damage (e.g. decreases in glutamate of 14.7% (p<0.05) and 12.3% (p<0.01) in the cortex and hippocampus, respectively), membrane disruption (e.g. decreases in the total level of phosphocholine and glycerophosphocholine of 23.0% (p<0.01) and 19.0% (p<0.01) in the cortex and hippocampus, respectively) and neuronal injury (e.g. decreases in N-acetylaspartate of 15.3% (p<0.01) and 9.7% (p>0.05) in the cortex and hippocampus, respectively). Significant changes in the overall pattern of NMR-observable metabolites using principal components analysis were also observed in TBI animals. Although TBI clearly had an effect on the metabolic profile found in brain tissue, no clear effects could be discerned in plasma samples. This was at least partly due to large variability in dominant glucose and lactate peaks in plasma. However, disruption of the blood-brain barrier and the subsequent movement of metabolites from brain into blood may have been relatively small and below the detection limits of our analytical procedures. Overall, these data indicate that TBI results in several significant changes in brain metabolism early after trauma and that a metabolomic approach based on (1)H NMR spectroscopy can provide a metabolic profile comprising several metabolite classes and allow for relative quantification of such changes within specific brain regions. The results also provide support for further development and application of metabolomic technologies for studying TBI and for the utilization of multivariate models for classifying the extent of trauma within an individual.