Introduction: In children, traumatic brain injury (TBI) is the leading cause of life-long disabilities. Glucose is the primary substrate for brain energy and metabolism however, TBI results in dysregulation of brain oxidative glucose metabolism within the hours after the injury. While the time course of these metabolic changes has been well described in the adult brain, there is little information about temporal and spatial cerebral metabolic changes following TBI in the developing brain.
Methods: We used controlled cortical injury (CCI) as a model of focal, moderate-to-severe traumatic brain injury. In brief, immature rats (21 days old) underwent a left parieto-temporal craniotomy followed by CCI injury. 24 hours, 3-days, and 7-days after the injury, the cortex and hippocampus from the injured (ipsilateral) and contralateral sides of the brain were dissected and used for biochemical assays.
Results: To determine the effects of TBI on oxidative glucose metabolism in the developing brain, we first measured the expression of genes involved in glucose metabolism. We found that after TBI, glycolytic genes were upregulated, with an early rise in the ipsilateral hippocampus and gradual sustained upregulation in the ipsilateral cortex. Moreover, pyruvate metabolism genes were upregulated by 24 hours and TCA cycle genes at 3-days after TBI. These data suggest that TBI induces temporal and spatial transcriptional changes of metabolic genes in the developing brain. The developing brain utilizes systemic glucose as fuel for energy production. Thus, we determine the effect of TBI on glucose uptake using 2-Deoxyglucose. We found that across all the timepoints, there was a significant decrease in glucose uptake in the injured ipsilateral cortex compared to craniotomy only or anesthesia only controls. Interestingly, uptake of 2-Deoxyglucose was decreased in the contralateral cortex of TBI brain on day 3 post-injury. Similarly, in hippocampus 2-deoxyglucose uptake was decreased in both ipsilateral (injured) and contralateral sides on day 3 post-TBI, but recovered by day 7. Next, we measured the oxidation rates (14CO2 production) of multiple substrates involved in glucose metabolism. We determined that TBI had no effect on 14C-U-glucose oxidation compared to controls across all time points in both cortex and hippocampus. Surprisingly, oxidation rates of 14C-U-lactate and 1-14C-pyruvate were significantly decreased in both ipsilateral (injured) cortex and hippocampus at 24 hours and 3-days post-TBI. Glucose and lactate converge to pyruvate, which is then shuttled into the mitochondria to enter the TCA cycle. The changes in oxidation of lactate and pyruvate but not glucose suggest that glucose may be redirected to other metabolic pathways such as the pentose phosphate pathway (PPP), a pathway essential for the synthesis of nucleic acid precursors, production of NADPH, regeneration of glutathione, and contributes to lipid synthesis.
Conclusions: Altogether, our data show that TBI in the developing brain results in temporal and spatial alterations in glucose oxidative metabolism. Further experiments should be performed to characterize the changes in PPP metabolic flux after TBI in the developing brain and to determine whether these changes are adaptive or maladaptive.
