Oxidative stress accompanies HIF1-dependent impairment of glucose metabolism in the hippocampus of adult rats survived prenatal severe hypoxia

Abstract

Abstract Many socially significant diseases are associated with disorders of prenatal development. Previously, we have shown the pathological role of hypoxia inducible factor HIF1 in post-hypoxic reoxygenation. This study aims to investigate the effect of prenatal severe hypoxia (PSH) on HIF1α protein expression as well as on HIF1-dependent activity of the pentose phosphate pathway (PPP) and anaerobic glycolysis in the hippocampus (HPC) of the offspring reached adulthood. We showed that PSH causes a stable increase in the content of HIF1α protein in the HPC which was accompanied by an increase in the efficacy of anaerobic glycolysis. This was testified by increased LDH activity and lactate concentration. At the same time, the amounts of G6PD, NADPH and also reduced glutathione decreased in the HPC of PSH rats, whereas the concentration of an oxidative stress marker, MDA, exceeded the control values. In a series of experiments using the model of emotional stress "learned helplessness" or the model of severe hypoxic stress, it was shown that in the HPC of control rats there was an increase in the amount of HIF1α in response to stress, which was also accompanied by more efficient anaerobic glycolysis and decreased efficacy of the PPP similar to the intact PSH rats. In the PSH rats, in turn, emotional stress resulted even in higher HIF1α levels without affecting glycolysis and PPP. Therefore, the increased content and activity of the transcription factor HIF1α in the HPC of adult rats exposed to prenatal hypoxia leads to the imbalance between glycolysis and the PPP which is accompanied by oxidative stress.