Neuroprotective Mechanism of Hypoxic Post-conditioning Involves HIF1-Associated Regulation of the Pentose Phosphate Pathway in Rat Brain
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Post-conditioning is exposure of an injured organism to the same harmful factors but of milder intensity which mobilizes endogenous protective mechanisms. Recently, we have developed a novel noninvasive post-conditioning (PostC) protocol involving three sequential episodes of mild hypobaric hypoxia which exerts pronounced neuroprotective action. In particular, it prevents development of pathological cascades caused by severe hypobaric hypoxia (SH) such as cellular loss, lipid peroxidation, abnormal neuroendocrine responses and behavioural deficit in experimental animals. Development of these post-hypoxic pathological effects has been associated with the delayed reduction of hypoxia-inducible factor 1 (HIF1) regulatory α-subunit levels in rat hippocampus, whereas PostC up-regulated it. The present study has been aimed at experimental examination of the hypothesis that intrinsic mechanisms underlying the neuroprotective and antioxidant effects of PostC involves HIF1-dependent stimulation of the pentose phosphate pathway (PPP). We have observed that SH leads to a decrease of glucose-6-phosphate dehydrogenase (G6PD) activity in the hippocampus and neocortex of rats as well as to a reduction in NADPH and total glutathione levels. This depletion of the antioxidant defense system together with excessive lipid peroxidation during the reoxygenation phase resulted in increased oxidative stress and massive cellular death observed after SH. In contrast, PostC led to normalization of G6PD activity, stabilization of the NADPH and total glutathione levels and thereby resulted in recovery of the cellular redox state and prevention of neuronal death. Our data suggest that stabilization of the antioxidant system via HIF1-associated PPP regulation represents an important neuroprotective mechanism enabled by PostC.
KeywordsSevere hypoxia Hypoxic post-conditioning HIF1 Pentose phosphate pathway Oxidative stress Neuroprotection
Hypoxia-inducible factor 1
Post-conditioning by mild hypobaric hypoxia
Reduced nicotinamide adenine dinucleotide phosphate
Pentose phosphate pathway
Reactive oxygen species
Severe hypobaric hypoxia
Terminal deoxynucleotidyl transferase (TdT) deoxyuridine triphosphate (dUTP) nick end labeling
Scientific research was performed at the Research park of Saint Petersburg State University, Resource Center for Ecological Safety Observatory and Resource Centre for Molecular and Cell Technologies. The work has been supported by Russian Foundation for Basic Research (RFBR) Grants Nos. 16-34-00027 and 16-04-00987 and Russian Program of State Academies GP-14 (Section 65).
OV was responsible for conducting the study and experimental design, performed experiments and wrote the paper. KS performed the experiments, contributed to experimental design and data analysis. ET and TG contributed to the experiments. AL analyzed the data statistically. OG, NE, and ER contributed to implementation of the study, data analysis and preparation of the paper. All authors read and approved the final manuscript.
Compliance with Ethical Standards
Conflict of interest
The authors declare no conflict of interest.
Animal experiments were carried out according to domestic regulations and the European Community Council Directive of 24 November 1986 (86/609/EEC) . Experimental protocols were approved by the local ethical committee.
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