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

Vetrovoy, O. V.; Sarieva, Kseniia; Galkina, Olga; Eschenko, Natalia; Lyanguzov, A. Yu.; Gluschenko, Tatjana; Tyulkova, E. I.; Рыбникова, Е. А.

doi:10.1007/s11064-018-2681-x

Cited by 19 publications

(11 citation statements)

References 71 publications

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“…Glycogenolysis activation, also named glycogen mobilization, is very important for maintaining physiological functions in the brain, such as synaptic transmission and sleep [ 7 , 8 ]. In addition, its degradation product, glucose-6-phosphate, can transform into antioxidant substrates, such as NADPH and glutathione via the pentose phosphate pathway (PPP) [ 9 , 10 ]. Previous studies have suggested that astrocytic glycogen accumulates excessively after I/R [ 11 – 13 ].…”

Section: Introductionmentioning

confidence: 99%

Astrocytic A1/A2 paradigm participates in glycogen mobilization mediated neuroprotection on reperfusion injury after ischemic stroke

Guo

Fan

Wang

et al. 2021

J Neuroinflammation

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Background Astrocytic glycogen works as an essential energy reserve for surrounding neurons and is reported to accumulate excessively during cerebral ischemia/reperfusion (I/R) injury. Our previous study found that accumulated glycogen mobilization exhibits a neuroprotective effect against I/R damage. In addition, ischemia could transform astrocytes into A1-like (toxic) and A2-like (protective) subtypes. However, the underlying mechanism behind accumulated glycogen mobilization-mediated neuroprotection in cerebral reperfusion injury and its relationship with the astrocytic A1/A2 paradigm is unknown. Methods Astrocytic glycogen phosphorylase, the rate-limiting enzyme in glycogen mobilization, was specifically overexpressed and knocked down in mice and in cultured astrocytes. The I/R injury was imitated using a middle cerebral artery occlusion/reperfusion model in mice and an oxygen–glucose deprivation/reoxygenation model in cultured cells. Alterations in A1-like and A2-like astrocytes and the expression of phosphorylated nuclear transcription factor-κB (NF-κB) and phosphorylated signal transducer and activator of transcription 3 (STAT3) were determined by RNA sequencing, immunofluorescence and immunoblotting. Metabolites, including glycogen, NADPH, glutathione and reactive oxygen species (ROS), were analyzed by biochemical analysis. Results Here, we observed that astrocytic glycogen mobilization inhibited A1-like astrocytes and enhanced A2-like astrocytes after reperfusion in an experimental ischemic stroke model in vivo and in vitro. In addition, glycogen mobilization could enhance the production of NADPH and glutathione by the pentose phosphate pathway (PPP) and reduce ROS levels during reperfusion. NF-κB inhibition and STAT3 activation caused by a decrease in ROS levels were responsible for glycogen mobilization-induced A1-like and A2-like astrocyte transformation after I/R. The astrocytic A1/A2 paradigm is closely correlated with glycogen mobilization-mediated neuroprotection in cerebral reperfusion injury. Conclusions Our data suggest that ROS-mediated NF-κB inhibition and STAT3 activation are the key pathways for glycogen mobilization-induced neuroprotection and provide a promising metabolic target for brain reperfusion injury in ischemic stroke.

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Section: Introductionmentioning

confidence: 99%

Astrocytic A1/A2 paradigm participates in glycogen mobilization mediated neuroprotection on reperfusion injury after ischemic stroke

Guo

Fan

Wang

et al. 2021

J Neuroinflammation

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“…We have investigated the role of HIF-1 using our animal model of pre-conditioning, by repetitive mild hypobaric hypoxia and assessing the HPA axis functioning. It was found that induction of brain hypoxic tolerance by pre-and post-conditioning was associated with two major events: an up-regulation of immediate HIF-1α expression [ 9 , 44 ] and potentiation of GC release in response to injurious exposures [ 9 , 19 ]. A number of recent comparative studies analyzing the effective (three-trial) and non-effective (one-trial or six-trial) pre-conditioning modes allowed us to suggest that both increased HIF-1α expression and potentiation of GC release are necessary for effective pre-conditioning [ 9 , 45 , 46 ].…”

Section: Glucocorticoids and Hypoxia-brain Tolerance And Cross-talk Mechanismsmentioning

confidence: 99%

Glucocorticoid-Dependent Mechanisms of Brain Tolerance to Hypoxia

Рыбникова

Nalivaeva

2021

IJMS

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Adaptation of organisms to stressors is coordinated by the hypothalamic-pituitary-adrenal axis (HPA), which involves glucocorticoids (GCs) and glucocorticoid receptors (GRs). Although the effects of GCs are well characterized, their impact on brain adaptation to hypoxia/ischemia is still understudied. The brain is not only the most susceptible to hypoxic injury, but also vulnerable to GC-induced damage, which makes studying the mechanisms of brain hypoxic tolerance and resistance to stress-related elevation of GCs of great importance. Cross-talk between the molecular mechanisms activated in neuronal cells by hypoxia and GCs provides a platform for developing the most effective and safe means for prevention and treatment of hypoxia-induced brain damage, including hypoxic pre- and post-conditioning. Taking into account that hypoxia- and GC-induced reprogramming significantly affects the development of organisms during embryogenesis, studies of the effects of prenatal and neonatal hypoxia on health in later life are of particular interest. This mini review discusses the accumulated data on the dynamics of the HPA activation in injurious and non-injurious hypoxia, the role of the brain GRs in these processes, interaction of GCs and hypoxia-inducible factor HIF-1, as well as cross-talk between GC and hypoxic signaling. It also identifies underdeveloped areas and suggests directions for further prospective studies.

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“…The ischemic injury protective effect of hypoxic preconditioning has recently been shown to also involve an inhibition of HSP27 degradation . Another report has implicated the involvement of the oxidative stress regulator hypoxia‐inducible factor 1 (HIF1) in maintaining the expression of G6PD that is reduced by severe hypobaric hypoxia . Interestingly, cannabidiol, an FDA‐approved nonpsychotropic compound from Cannabis sativa that has antiepileptic properties, attenuated ODG/R induced death of a cultured hippocampal neuronal cell line .…”

Section: G6pd and Brain Injurymentioning

confidence: 99%

“…68 Another report has implicated the involvement of the oxidative stress regulator hypoxia-inducible factor 1 (HIF1) in maintaining the expression of G6PD that is reduced by severe hypobaric hypoxia. 69 Interestingly, cannabidiol, an FDA-approved nonpsychotropic compound from Cannabis sativa that has antiepileptic properties, attenuated ODG/R induced death of a cultured hippocampal neuronal cell line. 70 Cannabidiol treatment resulted in G6PD activation and maintenance of the NADPH/NADP + ratio, and could be of therapeutic interest.…”

Section: G6pd and Brain Injurymentioning

confidence: 99%

Neuroprotection by glucose‐6‐phosphate dehydrogenase and the pentose phosphate pathway

Tang

2019

J of Cellular Biochemistry

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Glucose‐6‐phosphate dehydrogenase (G6PD), the rate limiting enzyme that channels glucose catabolism from glycolysis into the pentose phosphate pathway (PPP), is vital for the production of reduced nicotinamide adenine dinucleotide phosphate (NADPH) in cells. NADPH is in turn a substrate for glutathione reductase, which reduces oxidized glutathione disulfide to sulfhydryl glutathione. Best known for inherited deficiencies underlying acute hemolytic anemia due to elevated oxidative stress by food or medication, G6PD, and PPP activation have been associated with neuroprotection. Recent works have now provided more definitive evidence for G6PD's protective role in ischemic brain injury and strengthened its links to neurodegeneration. In Drosophila models, improved proteostasis and lifespan extension result from an increased PPP flux due to G6PD induction, which is phenocopied by transgenic overexpression of G6PD in neurons. Moderate transgenic expression of G6PD was also shown to improve healthspan in mouse. Here, the deciphered and implicated roles of G6PD and PPP in protection against brain injury, neurodegenerative diseases, and in healthspan/lifespan extensions are discussed together with an important caveat, namely NADPH oxidase (NOX) activity and the oxidative stress generated by the latter. Activation of G6PD with selective inhibition of NOX activity could be a viable neuroprotective strategy for brain injury, disease, and aging.

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

Cited by 19 publications

References 71 publications

Astrocytic A1/A2 paradigm participates in glycogen mobilization mediated neuroprotection on reperfusion injury after ischemic stroke

Astrocytic A1/A2 paradigm participates in glycogen mobilization mediated neuroprotection on reperfusion injury after ischemic stroke

Glucocorticoid-Dependent Mechanisms of Brain Tolerance to Hypoxia

Neuroprotection by glucose‐6‐phosphate dehydrogenase and the pentose phosphate pathway

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