TY - JOUR

T1 - Neuroprotective Mechanism of Hypoxic Post-conditioning Involves HIF1-Associated Regulation of the Pentose Phosphate Pathway in Rat Brain

AU - Vetrovoy, Oleg

AU - Sarieva, Ksenia

AU - Galkina, Olga

AU - Eschenko, Natalia

AU - Lyanguzov, Andrey

AU - Gluschenko, Tatjana

AU - Tyulkova, Ekaterina

AU - Rybnikova, Elena

PY - 2019/6/15

Y1 - 2019/6/15

N2 - 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.

AB - 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.

KW - HIF1

KW - Hypoxic post-conditioning

KW - Neuroprotection

KW - Oxidative stress

KW - Pentose phosphate pathway

KW - Severe hypoxia

KW - OXIDATIVE STRESS

KW - SEVERE HYPOBARIC HYPOXIA

KW - REPERFUSION INJURY

KW - ISCHEMIC POSTCONDITIONING PROTECTS

KW - CORTICAL-NEURONS

KW - GLUCOSE-METABOLISM

KW - SIGNALING PATHWAY

KW - HIF-1-ALPHA

KW - EXPRESSION

KW - CEREBRAL ISCHEMIA/REPERFUSION INJURY

UR - http://www.scopus.com/inward/record.url?scp=85056691987&partnerID=8YFLogxK

U2 - 10.1007/s11064-018-2681-x

DO - 10.1007/s11064-018-2681-x

M3 - Article

C2 - 30448928

AN - SCOPUS:85056691987

VL - 44

SP - 1425

EP - 1436

JO - Neurochemical Research

JF - Neurochemical Research

SN - 0364-3190

IS - 6

ER -