Metabolic perturbations after pediatric TBI: It's not just about glucose

Abstract

Improved patient survival following pediatric traumatic brain injury (TBI) has uncovered a currently limited understanding of both the adaptive and maladaptive metabolic perturbations that occur during the acute and long-term phases of recovery. While much is known about the redundancy of metabolic pathways that provide adequate energy and substrates for normal brain growth and development, the field is only beginning to characterize perturbations in these metabolic pathways after pediatric TBI. To date, the majority of studies have focused on dysregulated oxidative glucose metabolism after injury; however, the immature brain is well-equipped to use alternative substrates to fuel energy production, growth, and development. A comprehensive understanding of metabolic changes associated with pediatric TBI cannot be limited to investigations of glucose metabolism alone. All energy substrates used by the brain should be considered in developing nutritional and pharmacological interventions for pediatric head trauma. This review summarizes post-injury changes in brain metabolism of glucose, lipids, ketone bodies, and amino acids with discussion of the therapeutic potential of altering substrate utilization to improve pediatric TBI outcomes.

Keywords: Amino acids; Brain metabolism; Glucose; Ketones; Lipid; Neurometabolism; Oxidative metabolism; Traumatic brain injury (TBI).

Fig. 1.. Summary of brain macronutrient metabolism: Glycolysis, the pentose phosphate pathway, and mitochondrial oxidative metabolism of pyruvate, fatty acids, ketone bodies, and amino acids.

Cytosolic glucose can be catabolized by glycolysis or the pentose phosphate pathway. Pyruvate, the end-product of glycolysis can enter the mitochondrial matrix where it is oxidatively decarboxylated to acetyl-CoA by PDH in order to enter the TCA cycle. Long-chain fatty acids are converted to acyl-CoAs which traverse the mitochondrial membranes via the subsequent enzymatic activities of CPT1 and CPT2 in the carnitine shuttle. Ketone bodies such as β-hydroxybutyrate enter the TCA cycle as acetyl-CoA. Certain amino acids can enter the TCA cycle as acetyl-CoA, α-ketoglutarate, or succinyl-CoA. TCA cycle intermediates and NADPH and intermediates from the pentose phosphate pathway promote anabolic reactions in the cell. OMM = outer mitochondrial membrane; IMM = inner mitochondrial membrane; LDH = lactate dehydrogenase; CPT = carnitine palmitoyltransferase; MPC = mitochondrial pyruvate carrier; PDH = pyruvate dehydrogenase; PC = pyruvate carboxylase; OAA = oxaloacetate; TCA = tricarboxylic acid; CoA = coenzyme A; GABA = gamma-aminobutyric acid; BCAA = branched-chain amino acids

Fig. 2.. Glycolysis, glycogen metabolism, and the pentose phosphate pathway.

Glucose 6-phosphate, an intermediate in glycolysis, can be used for glycogen synthesis in astrocytes or can contribute to the pentose phosphate pathway.

Fig. 3.. Comparison of metabolic perturbations in pediatric and adult brain after TBI.

After injury both pediatric and adult brain have impaired mitochondrial oxidative metabolism of glucose as depicted by impaired pyruvate dehydrogenase (PDH). Both exhibit increased glycolysis and lactate production as indicated by the large red arrows. In injured adult brain, an increase in pentose phosphate pathway flux has been observed but this has not been studied in pediatric TBI. Ketone supplementation has been demonstrated to have beneficial metabolic and neurological outcomes in pre-clinical models of pediatric TBI but was not beneficial in adult TBI. BCAA supplementation in adult TBI improved outcomes but has not been studied in pediatric patients or pre-clinical models. The role of mitochondrial fatty acid oxidation during and after injury is not well understood nor is the role of gluconeogenesis nor mitochondrial pyruvate transport. The cell represented here reflects general metabolic perturbations that have been observed largely from studies of whole brain. The cell -type specificity of these metabolic responses to injury remains to be determined. Overall, multiple nutrients contribute to meeting brain energetic and biosynthetic demands, and those that are known to be altered in TBI are summarized here.