Mechanisms underlying
hypoxia-induced neuronal adaptation have not been fully elucidated. In the present study we investigated
glucose metabolism and the activities of glycolytic and TCA cycle
enzymes in cerebro-cortical neurons exposed to
hypoxia (3 days in 1% of O2) or normoxia (room air).
Hypoxia led to increased activities of LDH (194%), PK (90%), and HK (24%) and decreased activities of CS (15%) and GDH (34%). Neurons were incubated with [1-(13)C]
glucose for 45 and 120 min under normoxic or hypoxic (120 min only) conditions and 13C enrichment determined in the medium and
cell extract using 1H-{13C}-NMR. In
hypoxia-treated neurons [3-(13)C]
lactate release into the medium was 428% greater than in normoxia-treated controls (45-min normoxic incubation) and total flux through
lactate was increased by 425%. In contrast
glucose oxidation was reduced significantly in
hypoxia-treated neurons, even when expressed relative to total cellular
protein, which correlated with the reduced activities of the measured mitochondrial
enzymes. The results suggest that surviving neurons adapt to prolonged
hypoxia by up-regulation of glycolysis and down-regulation of oxidative energy metabolism, similar to certain other cell types. The factors leading to adaptation and survival for some neurons but not others remain to be determined.