Pharmacological HIF1 Inhibition Eliminates Downregulation of the Pentose Phosphate Pathway and Prevents Neuronal Apoptosis in Rat Hippocampus Caused by Severe Hypoxia

The pentose phosphate pathway (PPP) of glucose metabolism in the brain serves as a primary source of NADPH which in turn plays a crucial role in multiple cellular processes, including maintenance of redox homeostasis and antioxidant defense. In our model of protective mild hypobaric hypoxia in rats...

Full description

Saved in:
Bibliographic Details
Published in:Journal of molecular neuroscience Vol. 70; no. 5; pp. 635 - 646
Main Authors: Vetrovoy, Oleg, Sarieva, Kseniia, Lomert, Ekaterina, Nimiritsky, Peter, Eschenko, Natalia, Galkina, Olga, Lyanguzov, Andrey, Tyulkova, Ekaterina, Rybnikova, Elena
Format: Journal Article
Language:English
Published: New York Springer US 01.05.2020
Springer Nature B.V
Subjects:
Animals
Antioxidants
Apoptosis
Biomedical and Life Sciences
Biomedicine
Cell Biology
Depletion
Down-Regulation
Glucose
Glucose 6 phosphate dehydrogenase
Glucose metabolism
Glucosephosphate dehydrogenase
Glutathione
Hippocampus
Hippocampus - cytology
Hippocampus - drug effects
Hippocampus - metabolism
Homeostasis
Hypoxia
Hypoxia - drug therapy
Hypoxia - metabolism
Hypoxia-inducible factor 1
Hypoxia-Inducible Factor 1, alpha Subunit - antagonists & inhibitors
Hypoxia-Inducible Factor 1, alpha Subunit - genetics
Hypoxia-Inducible Factor 1, alpha Subunit - metabolism
Hypoxia-inducible factor 1a
Injection
Ischemia
Male
mRNA
NADP
Neurochemistry
Neurology
Neurons - metabolism
Neuroprotection
Neurosciences
Oxidative stress
Pentose
Pentose Phosphate Pathway
Proteomics
Rats
Rats, Wistar
Stimulators
Topotecan
Topotecan - pharmacology
Topotecan - therapeutic use
Pentose phosphate pathway
Oxidative stress
Neuroprotection
Severe hypoxia
Neuronal injury and loss
HIF1
ISSN:0895-8696, 1559-1166, 1559-1166
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:The pentose phosphate pathway (PPP) of glucose metabolism in the brain serves as a primary source of NADPH which in turn plays a crucial role in multiple cellular processes, including maintenance of redox homeostasis and antioxidant defense. In our model of protective mild hypobaric hypoxia in rats (3MHH), an inverse correlation between hypoxia-inducible factor-1 (HIF1) activity and mRNA levels of glucose-6-phosphate dehydrogenase (G6PD), the key enzyme of PPP, was observed. In the present study, it was demonstrated that severe hypobaric hypoxia (SH) induced short-term upregulation of HIF1 alpha-subunit (HIF1α) in the hippocampal CA1 subfield and decreased the activity of G6PD. The levels of NADPH were also reduced, promoting oxidative stress, triggering apoptosis, and neuronal loss. Injection of a HIF1 inhibitor (HIF1i), topotecan hydrochloride (5 mg/kg, i.p.), before SH prevented the upregulation of HIF1α and normalized G6PD activity. In addition, HIF1i injection caused an increase in NADPH levels, normalization of total glutathione levels and of the cellular redox status as well as suppression of free-radical and apoptotic processes. These results demonstrate a new molecular mechanism of post-hypoxic cerebral pathology development which involves HIF1-dependent PPP depletion and support a recently suggested injurious role of HIF1 activation in the acute phase of cerebral hypoxia/ischemia. Application of PPP stimulators in early post-hypoxic/ischemic period might represent a promising neuroprotective strategy. Graphical abstract HIF1-dependent down-regulation of the pentose phosphate pathway contributes to the hypoxia-induced oxidative stress and neuronal apoptosis in the rat hippocampus
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 14
content type line 23
ISSN:0895-8696
1559-1166
1559-1166
DOI:10.1007/s12031-019-01469-8