Glycolysis and the Pentose Phosphate Pathway after Human Traumatic Brain Injury: Microdialysis Studies Using 1,2-¹³C₂ Glucose

Abstract

Increased 'anaerobic' glucose metabolism is observed after traumatic brain injury (TBI) attributed to increased glycolysis. An alternative route is the pentose phosphate pathway (PPP), which generates putatively protective and reparative molecules. To compare pathways we employed microdialysis to perfuse 1,2-(13)C2 glucose into the brains of 15 TBI patients and macroscopically normal brain in six patients undergoing surgery for benign tumors, and to simultaneously collect products for nuclear magnetic resonance (NMR) analysis. (13)C enrichment for glycolytic 2,3-(13)C2 lactate was the median 5.4% (interquartile range (IQR) 4.6-7.5%) in TBI brain and 4.2% (2.4-4.4%) in 'normal' brain (P<0.01). The ratio of PPP-derived 3-(13)C lactate to glycolytic 2,3-(13)C2 lactate was median 4.9% (3.6-8.2%) in TBI brain and 6.7% (6.3-8.9%) in 'normal' brain. An inverse relationship was seen for PPP-glycolytic lactate ratio versus PbtO2 (r=-0.5, P=0.04) in TBI brain. Thus, glycolytic lactate production was significantly greater in TBI than 'normal' brain. Several TBI patients exhibited PPP-lactate elevation above the 'normal' range. There was proportionally greater PPP-derived lactate production with decreasing PbtO2. The study raises questions about the roles of the PPP and glycolysis after TBI, and whether they can be manipulated to achieve a better outcome. This study is the first direct comparison of glycolysis and PPP in human brain.

An investigation of neuroinjury biomarkers after sport-related concussion: from the subacute phase to clinical recovery

“…Median total symptoms and symptom severity were 7.5 (IQR 5 -13) and 12.0 (IQR 5.3 -22.6), respectively, at the time of medical evaluation. At the time of blood sampling, the median total symptoms reported by athletes with SRC was 5 (IQR 4-11), and the median symptom severity was 8 (IQR [4][5][6][7][8][9][10][11][12][13][14][15][16][17]. At the time of blood sampling, compared to healthy controls, athletes with SRC had significantly higher total symptoms scores (median score = 5.0 vs. 3.0 respectively; p = 0.04, data not shown) but not symptom severity scores.…”

“…In humans, recent studies employing advanced neuroimaging techniques support these early findings (3,(8)(9)(10)(11)), yet our understanding of secondary injury after sport-related concussion (SRC) remains limited (12).…”

Microdialysis Monitoring in Clinical Traumatic Brain Injury and Its Role in Neuroprotective Drug Development

“…Delivery of 13 C-labelled substrates focally into brain via the microdialysis catheter and simultaneous recovery of the 13 Clabelled metabolites in the emerging microdialysate has been successfully performed in TBI patients (28,96,97). In preclinical experiments, retrodialysis has recently been shown to successfully deliver dexamethasone directly in both experimental TBI with ameliorating effects (98) and to transgenic animals expressing decreased microglia activity (99).…”

Microdialysate concentration changes do not provide sufficient information to evaluate metabolic effects of lactate supplementation in brain-injured patients

“…Modified from Figure 1 control patients. 100 Less lactate was subsequently found to be generated from the pentose shunt compared with glycolysis in TBI patients, 101 but these pathway fluxes may vary with severity and progression of injury. Inhibition of glycolysis by lactate will impair pentose shunt flux because glucose-derived carbon re-enters the glycolytic pathway upstream of the metabolic steps requiring action of phosphofructokinase and NAD þ availability ( Figure 5).…”