Metabolic alterations induced by ischemia in primary cultures of astrocytes: merging ¹³C NMR spectroscopy and metabolic flux analysis

Abstract

J. Neurochem. (2010) 113, 735–748. Abstract Disruption of brain energy metabolism is the hallmark of cerebral ischemia, a major cause of death worldwide. Astrocytes play a key role in the regulation of brain metabolism and their vulnerability to ischemia has been described. Aiming to quantify the effects of an ischemic insult in astrocytic metabolism, primary cultures of astrocytes were subjected to 5 h of oxygen and glucose deprivation in a bioreactor. Flux distributions, before and after ischemia, were estimated by metabolic flux analysis using isotopic information and the consumption/secretion rates of relevant extracellular metabolites as constraints. During ischemia and early recovery, 30% of cell death was observed; several metabolic alterations were also identified reflecting a metabolic response by the surviving cells. In the early recovery (∼10 h), astrocytes up‐regulated glucose utilization by 30% and increased the pentose phosphate pathway and tricarboxylic acid cycle fluxes by three and twofold, respectively. Additionally, a two to fivefold enhancement in branched‐chain amino acids catabolism suggested the importance of anaplerotic molecules to the fast recovery of the energetic state, which was corroborated by measured cellular ATP levels. Glycolytic metabolism was predominant in the late recovery. In summary, this work demonstrates that changes in fluxes of key metabolic pathways are implicated in the recovery from ischemia in astrocytes.

The pentose phosphate pathway: An antioxidant defense and a crossroad in tumor cell fate

“…In this pathological condition the inhibition of PPP by 6-AN reduces the cardiac damage [51]. In contrast, in the early brain postischemic phase, surviving astrocytes significantly increase the metabolic flux through glycolysis and PPP, to produce ATP and NADPH, which in this case reduces the oxidative damage [52].…”

Expression Changes in Lactate and Glucose Metabolism and Associated Transporters in Basal Ganglia following Hypoxic-Ischemic Reperfusion Injury in Piglets

“…Neurons then take up lactate through membrane-bound MCT-2, which is then converted to acetone by lactate dehydrogenase, and acetone is then metabolized aerobically via the citric acid cycle to produce energy. [5][6][7][8][9] Moreover, lactate is closely associated with glucose metabolism, but a correlation with dynamic metabolic changes remains unclear. In vivo glucose metabolism in the brain is evaluated by [ 18 F] fluorodeoxyglucose imaging.…”

Measurement of Lactate Content and Amide Proton Transfer Values in the Basal Ganglia of a Neonatal Piglet Hypoxic-Ischemic Brain Injury Model Using MRI

“…Normally, brain activities are primarily supported by energy produced from the aerobic metabolism of glucose. [1][2][3] In a physiologic state, 90%-95% of brain energy is consumed by neurons, but 80% of glucose use happens in astrocytes, which suggests that a glucose mesostate released by astrocytes is absorbed and used by neurons to support their high energy consumption. A study 4 has shown that during glucose metabolism in the brain, lactate is a carrier of energy and facilitates interaction between astrocytes and neurons.…”