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

Abstract

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.

Authors+Show Affiliations

Laboratory of Regulation of Brain Neuron Functions, Pavlov Institute of Physiology, Russian Academy of Sciences, Makarova emb. 6, 199034, Saint Petersburg, Russia. vov210292@yandex.ru. Department of Biochemistry, Faculty of Biology, Saint Petersburg State University, Universitetskaya emb. 7-9, 199034, Saint Petersburg, Russia. vov210292@yandex.ru.Laboratory of Regulation of Brain Neuron Functions, Pavlov Institute of Physiology, Russian Academy of Sciences, Makarova emb. 6, 199034, Saint Petersburg, Russia.Laboratory of Cell Biology in Culture, Institute of Cytology, Russian Academy of Sciences, Tihoretsky pr. 4, 194064, Saint Petersburg, Russia.Institute for Regenerative Medicine, Medical Research and Education Center, Lomonosov Moscow State University, Lomonosov Ave. 27-10, 119192, Moscow, Russia. Faculty of Medicine, Lomonosov Moscow State University, Lomonosov Ave. 31-5, 119192, Moscow, Russia.Department of Biochemistry, Faculty of Biology, Saint Petersburg State University, Universitetskaya emb. 7-9, 199034, Saint Petersburg, Russia.Department of Biochemistry, Faculty of Biology, Saint Petersburg State University, Universitetskaya emb. 7-9, 199034, Saint Petersburg, Russia.Department of Biochemistry, Faculty of Biology, Saint Petersburg State University, Universitetskaya emb. 7-9, 199034, Saint Petersburg, Russia.Laboratory of Regulation of Brain Neuron Functions, Pavlov Institute of Physiology, Russian Academy of Sciences, Makarova emb. 6, 199034, Saint Petersburg, Russia.Laboratory of Regulation of Brain Neuron Functions, Pavlov Institute of Physiology, Russian Academy of Sciences, Makarova emb. 6, 199034, Saint Petersburg, Russia.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31865524

Citation

Vetrovoy, Oleg, et al. "Pharmacological HIF1 Inhibition Eliminates Downregulation of the Pentose Phosphate Pathway and Prevents Neuronal Apoptosis in Rat Hippocampus Caused By Severe Hypoxia." Journal of Molecular Neuroscience : MN, 2019.
Vetrovoy O, Sarieva K, Lomert E, et al. Pharmacological HIF1 Inhibition Eliminates Downregulation of the Pentose Phosphate Pathway and Prevents Neuronal Apoptosis in Rat Hippocampus Caused by Severe Hypoxia. J Mol Neurosci. 2019.
Vetrovoy, O., Sarieva, K., Lomert, E., Nimiritsky, P., Eschenko, N., Galkina, O., ... Rybnikova, E. (2019). Pharmacological HIF1 Inhibition Eliminates Downregulation of the Pentose Phosphate Pathway and Prevents Neuronal Apoptosis in Rat Hippocampus Caused by Severe Hypoxia. Journal of Molecular Neuroscience : MN, doi:10.1007/s12031-019-01469-8.
Vetrovoy O, et al. Pharmacological HIF1 Inhibition Eliminates Downregulation of the Pentose Phosphate Pathway and Prevents Neuronal Apoptosis in Rat Hippocampus Caused By Severe Hypoxia. J Mol Neurosci. 2019 Dec 21; PubMed PMID: 31865524.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pharmacological HIF1 Inhibition Eliminates Downregulation of the Pentose Phosphate Pathway and Prevents Neuronal Apoptosis in Rat Hippocampus Caused by Severe Hypoxia. AU - Vetrovoy,Oleg, AU - Sarieva,Kseniia, AU - Lomert,Ekaterina, AU - Nimiritsky,Peter, AU - Eschenko,Natalia, AU - Galkina,Olga, AU - Lyanguzov,Andrey, AU - Tyulkova,Ekaterina, AU - Rybnikova,Elena, Y1 - 2019/12/21/ PY - 2019/08/26/received PY - 2019/12/12/accepted PY - 2019/12/23/entrez PY - 2019/12/23/pubmed PY - 2019/12/23/medline KW - HIF1 KW - Neuronal injury and loss KW - Neuroprotection KW - Oxidative stress KW - Pentose phosphate pathway KW - Severe hypoxia JF - Journal of molecular neuroscience : MN JO - J. Mol. Neurosci. N2 - 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. SN - 1559-1166 UR - https://www.unboundmedicine.com/medline/citation/31865524/Pharmacological_HIF1_Inhibition_Eliminates_Downregulation_of_the_Pentose_Phosphate_Pathway_and_Prevents_Neuronal_Apoptosis_in_Rat_Hippocampus_Caused_by_Severe_Hypoxia L2 - https://dx.doi.org/10.1007/s12031-019-01469-8 DB - PRIME DP - Unbound Medicine ER -