Delayed cerebral oxidative glucose metabolism after traumatic brain injury in young rats

Abstract

Abbreviations used: ASP C3, [3][4][5][6][7][8][9][10][11][12][13] C]aspartate; PC, pyruvate carboxylase; PDHC, pyruvate dehydrogenase complex; TBI, traumatic brain injury; TCA, tricarboxylic acid. AbstractTraumatic brain injury (TBI) results in a cerebral metabolic crisis that contributes to poor neurologic outcome. The aim of this study was to characterize changes in oxidative glucose metabolism in early periods after injury in the brains of immature animals. At 5 h after controlled cortical impact TBI or sham surgery to the left cortex, 21-22 day old rats were injected intraperitoneally with [1,[6][7][8][9][10][11][12][13] C]glucose and brains removed 15, 30 and 60 min later and studied by ex vivo 13 C-NMR spectroscopy. Oxidative metabolism, determined by incorporation of 13 C into glutamate, glutamine and GABA over 15-60 min, was significantly delayed in both hemispheres of brain from TBI rats. The most striking delay was in labeling of the C4 position of glutamate from neuronal metabolism of glucose in the injured, ipsilateral hemisphere which peaked at 60 min, compared with the contralateral and sham-operated brains, where metabolism peaked at 30 and 15 min, respectively. Our findings indicate that (i) neuronal-specific oxidative metabolism of glucose at 5-6 h after TBI is delayed in both injured and contralateral sides compared with sham brain; (ii) labeling from metabolism of glucose via the pyruvate carboxylase pathway in astrocytes was also initially delayed in both sides of TBI brain compared with sham brain; (iii) despite this delayed incorporation, at 6 h after TBI, both sides of the brain showed apparent increased neuronal and glial metabolism, reflecting accumulation of labeled metabolites, suggesting impaired malate aspartate shuttle activity. The presence of delayed metabolism, followed by accumulation of labeled compounds is evidence of severe alterations in homeostasis that could impair mitochondrial metabolism in both ipsilateral and contralateral sides of brain after TBI. However, ongoing oxidative metabolism in mitochondria in injured brain suggests that there is a window of opportunity for therapeutic intervention up to at least 6 h after injury. Keywords:13 C-NMR spectroscopy, GABA, glucose, gluta- et al. 2005) reported significant increases in brain lactate and glutamine production as early as 3.5 h after TBI in immobilized adult rats. Investigations on the effects of TBI on energy metabolism of the immature brain are limited, despite the prevalence of TBI in children. Nevertheless, brain mitochondrial respiration and pyruvate dehydrogenase complex activity levels are reduced within 4 h after TBI in immature rats (Robertson et al. 2007). A recent 1 H-NMR study reported increased lactate at 4 h, and decreased N-acetylaspartate at 24 h and 7 days after TBI providing further evidence of mitochondrial dysfunction after TBI in immature brain (Casey et al. 2008).The aim of this study was to determine glycolytic and oxidative glucose metabolism and neurotransmitter synthesis using 13 C-NMR spec...

Age-Related Mitochondrial Changes after Traumatic Brain Injury

“…There is ongoing research in experimental TBI to define the age threshold and injury severity that coincides with findings of higher morbidity and mortality. Cognitive and morphological differences have been previously noted in aged experimental brain-injured rats (Fan et al, 2003;Hamm et al, 1991;Hoane et al, 2004;Shah et al, 2006;Shao et al, 2006), and also if injury occurs in the very early stages of development (Casey et al, 2008;Robertson et al, 2007Robertson et al, , 2009Scafidi et al, 2009).…”

Alteration of Interaction Between Astrocytes and Neurons in Different Stages of Diabetes: a Nuclear Magnetic Resonance Study Using [1-13C]Glucose and [2-13C]Acetate

“…Astrocytes have crucial functions in the brain, including absorbing and disposing glutamate (Glu) from the synaptic cleft, maintaining pH and appropriate concentrations of K + and other ions in the interstitial milieu, and providing energy substrates for neurons [16]. Increased astrocyte-specific glial fibrillary acidic protein (GFAP) expression has been found in the cortex and hippocampus of STZ-induced diabetic rats [17].…”

Cerebral Glucose Metabolism in an Immature Rat Model of Pediatric Traumatic Brain Injury

“…Alterations in brain metabolism and mitochondrial function have been identified in both experimental studies in immature animal models [3][4][5][6][7] and in infants and children after TBI. [3][4][5][6][7][8][9][10] These alterations can occur early after injury and persist for days or weeks.…”