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Targeting Reductive Stress With Oxygen Enrichment Rescues Hippocampus-Dependent Memory Impairment after Acute Hypobaric Hypoxia.

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Τίτλος: Targeting Reductive Stress With Oxygen Enrichment Rescues Hippocampus-Dependent Memory Impairment after Acute Hypobaric Hypoxia.
Συγγραφείς: Ma J; School of Biomedical Engineering, The Air Force Military Medical University, 710032 Xi'an, Shaanxi, China.; School of Medicine, Xiamen University, 361102 Xiamen, Fujian, China., Miao M; Affiliated Hospital of Medical School, Jinling Hospital, Nanjing University, 210093 Nanjing, Jiangsu, China., Liu X; School of Biomedical Engineering, The Air Force Military Medical University, 710032 Xi'an, Shaanxi, China., Tian X; School of Biomedical Engineering, The Air Force Military Medical University, 710032 Xi'an, Shaanxi, China., Zhang C; School of Biomedical Engineering, The Air Force Military Medical University, 710032 Xi'an, Shaanxi, China., Li Y; School of Biomedical Engineering, The Air Force Military Medical University, 710032 Xi'an, Shaanxi, China., Zhao C; School of Biomedical Engineering, The Air Force Military Medical University, 710032 Xi'an, Shaanxi, China., Liu J; School of Biomedical Engineering, The Air Force Military Medical University, 710032 Xi'an, Shaanxi, China., Xie K; School of Biomedical Engineering, The Air Force Military Medical University, 710032 Xi'an, Shaanxi, China., Tang C; School of Biomedical Engineering, The Air Force Military Medical University, 710032 Xi'an, Shaanxi, China.; Shaanxi Provincial Key Laboratory of Bioelectromagnetic Detection and Intelligent Perception, 710032 Xi'an, Shaanxi, China., Zhai M; School of Biomedical Engineering, The Air Force Military Medical University, 710032 Xi'an, Shaanxi, China.; Shaanxi Provincial Key Laboratory of Bioelectromagnetic Detection and Intelligent Perception, 710032 Xi'an, Shaanxi, China.
Πηγή: Frontiers in bioscience (Landmark edition) [Front Biosci (Landmark Ed)] 2026 Sep 17; Vol. 31 (9), pp. 54346.
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: IMR Press Country of Publication: Singapore NLM ID: 101612996 Publication Model: Print Cited Medium: Internet ISSN: 2768-6698 (Electronic) Linking ISSN: 27686698 NLM ISO Abbreviation: Front Biosci (Landmark Ed) Subsets: MEDLINE
Imprint Name(s): Publication: 2022- : Singapore : IMR Press
Original Publication: Searington, NY : Frontiers in Bioscience
Ιατρικοί όροι (MeSH): Hypoxia*/metabolism , Hypoxia*/complications , Hippocampus*/metabolism , Hippocampus*/physiopathology , Hippocampus*/pathology , Oxygen*/metabolism , Memory Disorders*/metabolism , Memory Disorders*/etiology , Memory Disorders*/therapy, NF-E2-Related Factor 2/metabolism ; Antioxidants/metabolism ; Glutathione/metabolism ; Animals ; Oxidative Stress ; Rats ; Male ; Oxidation-Reduction ; Apoptosis ; Rats, Sprague-Dawley
Περίληψη: Background: High-altitude hypobaric hypoxia is known to impair cognitive function, but the underlying mechanistic role of impaired redox homeostasis in this context remains incompletely understood. This study investigated whether acute hypobaric hypoxia induces oxidative stress and redox dysregulation in the hippocampus, and whether oxygen enrichment can mitigate these impairments by restoring redox homeostasis.
Methods: Spatial memory was assessed using the Morris water maze. Additionally, hippocampal morphology, redox status (including glutathione/oxidized glutathione [GSH/GSSG], the reduced nicotinamide adenine dinucleotide/oxidized nicotinamide adenine dinucleotide [NADH/NAD+], and the reduced nicotinamide adenine dinucleotide phosphate/oxidized nicotinamide adenine dinucleotide phosphate [NADPH/NADP+] ratios, as well as antioxidant enzyme activity levels), and associated molecular pathways were analyzed.
Results: Following 3 days of hypoxia exposure, rats exhibited impaired spatial memory retention, increased neuronal apoptosis, and reduced neuronal viability in the hippocampal cornu ammonis 1 [CA1] region. The hippocampus displayed significantly altered redox status, characterized by elevated GSH/GSSG, NADH/NAD+, and NADPH/NADP+ ratios, upregulated antioxidant enzymes (superoxide dismutase [SOD], catalase [CAT], and glutathione peroxidase [GPX]), and decreased superoxide levels. These changes are consistent with an adaptive nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidant response and a shift toward a reductive state. Notably, oxygen enrichment rescued cognitive deficits, attenuated neuronal apoptosis, and normalized redox ratios and the microtubule-associated protein 1A/1B-light chain 3-II/microtubule-associated protein 1A/1B-light chain 3-I (LC3B-II/ LC3B-I) ratio.
Conclusions: Hypoxia-induced redox dysregulation is closely associated with cognitive impairment. Oxygen enrichment alleviates these deficits by modulating the Nrf2-mediated adaptive response and restoring redox homeostasis, thereby supporting further investigation of oxygen enrichment as a potential neuroprotective strategy.
(Copyright: © 2026 The Author(s). Published by IMR Press.)
Competing Interests: The authors declare no conflicts of interest. Gene Denovo Biotechnology (Guangzhou, Guangdong, China) provided technical assistance with RNA sequencing and data analysis only and had no role in the study design, interpretation of the results, preparation of the manuscript, or the decision to submit the manuscript for publication.
Grant Information: 2022JQ-827 Youth Fund of the Shaanxi Province Natural Science Foundation; 2021JH053 Industry-Education-Research Innovation Fund of Chinese University
Contributed Indexing: Keywords: Nrf2; hippocampus; hypobaric hypoxia; oxygen enrichment; redox homeostasis; spatial memory
Substance Nomenclature: S88TT14065 (Oxygen)
0 (NF-E2-Related Factor 2)
0 (Antioxidants)
GAN16C9B8O (Glutathione)
Entry Date(s): Date Created: 20260930 Date Completed: 20260930 Latest Revision: 20260930
Update Code: 20260930
DOI: 10.31083/FBL54346
PMID: 42811973
Βάση Δεδομένων: MEDLINE
FullText Text:
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  Label: Title
  Group: Ti
  Data: Targeting Reductive Stress With Oxygen Enrichment Rescues Hippocampus-Dependent Memory Impairment after Acute Hypobaric Hypoxia.
– Name: Author
  Label: Authors
  Group: Au
  Data: <searchLink fieldCode="AU" term="%22Ma+J%22">Ma J</searchLink>; School of Biomedical Engineering, The Air Force Military Medical University, 710032 Xi'an, Shaanxi, China.; School of Medicine, Xiamen University, 361102 Xiamen, Fujian, China.<br /><searchLink fieldCode="AU" term="%22Miao+M%22">Miao M</searchLink>; Affiliated Hospital of Medical School, Jinling Hospital, Nanjing University, 210093 Nanjing, Jiangsu, China.<br /><searchLink fieldCode="AU" term="%22Liu+X%22">Liu X</searchLink>; School of Biomedical Engineering, The Air Force Military Medical University, 710032 Xi'an, Shaanxi, China.<br /><searchLink fieldCode="AU" term="%22Tian+X%22">Tian X</searchLink>; School of Biomedical Engineering, The Air Force Military Medical University, 710032 Xi'an, Shaanxi, China.<br /><searchLink fieldCode="AU" term="%22Zhang+C%22">Zhang C</searchLink>; School of Biomedical Engineering, The Air Force Military Medical University, 710032 Xi'an, Shaanxi, China.<br /><searchLink fieldCode="AU" term="%22Li+Y%22">Li Y</searchLink>; School of Biomedical Engineering, The Air Force Military Medical University, 710032 Xi'an, Shaanxi, China.<br /><searchLink fieldCode="AU" term="%22Zhao+C%22">Zhao C</searchLink>; School of Biomedical Engineering, The Air Force Military Medical University, 710032 Xi'an, Shaanxi, China.<br /><searchLink fieldCode="AU" term="%22Liu+J%22">Liu J</searchLink>; School of Biomedical Engineering, The Air Force Military Medical University, 710032 Xi'an, Shaanxi, China.<br /><searchLink fieldCode="AU" term="%22Xie+K%22">Xie K</searchLink>; School of Biomedical Engineering, The Air Force Military Medical University, 710032 Xi'an, Shaanxi, China.<br /><searchLink fieldCode="AU" term="%22Tang+C%22">Tang C</searchLink>; School of Biomedical Engineering, The Air Force Military Medical University, 710032 Xi'an, Shaanxi, China.; Shaanxi Provincial Key Laboratory of Bioelectromagnetic Detection and Intelligent Perception, 710032 Xi'an, Shaanxi, China.<br /><searchLink fieldCode="AU" term="%22Zhai+M%22">Zhai M</searchLink>; School of Biomedical Engineering, The Air Force Military Medical University, 710032 Xi'an, Shaanxi, China.; Shaanxi Provincial Key Laboratory of Bioelectromagnetic Detection and Intelligent Perception, 710032 Xi'an, Shaanxi, China.
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  Data: <searchLink fieldCode="JN" term="%22101612996%22">Frontiers in bioscience (Landmark edition)</searchLink> [Front Biosci (Landmark Ed)] 2026 Sep 17; Vol. 31 (9), pp. 54346.
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  Data: <i>Publisher: </i><searchLink fieldCode="PB" term="%22IMR+Press%22">IMR Press </searchLink><i>Country of Publication: </i>Singapore <i>NLM ID: </i>101612996 <i>Publication Model: </i>Print <i>Cited Medium: </i>Internet <i>ISSN: </i>2768-6698 (Electronic) <i>Linking ISSN: </i><searchLink fieldCode="IS" term="%2227686698%22">27686698 </searchLink><i>NLM ISO Abbreviation: </i>Front Biosci (Landmark Ed) <i>Subsets: </i>MEDLINE
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  Data: <i>Publication</i>: 2022- : Singapore : IMR Press<br /><i>Original Publication</i>: Searington, NY : Frontiers in Bioscience
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  Data: <searchLink fieldCode="MM" term="%22Hypoxia%22">Hypoxia*</searchLink>/<searchLink fieldCode="MM" term="%22Hypoxia+metabolism%22">metabolism</searchLink> <br /><searchLink fieldCode="MM" term="%22Hypoxia%22">Hypoxia*</searchLink>/<searchLink fieldCode="MM" term="%22Hypoxia+complications%22">complications</searchLink> <br /><searchLink fieldCode="MM" term="%22Hippocampus%22">Hippocampus*</searchLink>/<searchLink fieldCode="MM" term="%22Hippocampus+metabolism%22">metabolism</searchLink> <br /><searchLink fieldCode="MM" term="%22Hippocampus%22">Hippocampus*</searchLink>/<searchLink fieldCode="MM" term="%22Hippocampus+physiopathology%22">physiopathology</searchLink> <br /><searchLink fieldCode="MM" term="%22Hippocampus%22">Hippocampus*</searchLink>/<searchLink fieldCode="MM" term="%22Hippocampus+pathology%22">pathology</searchLink> <br /><searchLink fieldCode="MM" term="%22Oxygen%22">Oxygen*</searchLink>/<searchLink fieldCode="MM" term="%22Oxygen+metabolism%22">metabolism</searchLink> <br /><searchLink fieldCode="MM" term="%22Memory+Disorders%22">Memory Disorders*</searchLink>/<searchLink fieldCode="MM" term="%22Memory+Disorders+metabolism%22">metabolism</searchLink> <br /><searchLink fieldCode="MM" term="%22Memory+Disorders%22">Memory Disorders*</searchLink>/<searchLink fieldCode="MM" term="%22Memory+Disorders+etiology%22">etiology</searchLink> <br /><searchLink fieldCode="MM" term="%22Memory+Disorders%22">Memory Disorders*</searchLink>/<searchLink fieldCode="MM" term="%22Memory+Disorders+therapy%22">therapy</searchLink><br /><searchLink fieldCode="MH" term="%22NF-E2-Related+Factor+2%22">NF-E2-Related Factor 2</searchLink>/<searchLink fieldCode="MH" term="%22NF-E2-Related+Factor+2+metabolism%22">metabolism</searchLink> ; <searchLink fieldCode="MH" term="%22Antioxidants%22">Antioxidants</searchLink>/<searchLink fieldCode="MH" term="%22Antioxidants+metabolism%22">metabolism</searchLink> ; <searchLink fieldCode="MH" term="%22Glutathione%22">Glutathione</searchLink>/<searchLink fieldCode="MH" term="%22Glutathione+metabolism%22">metabolism</searchLink> ; <searchLink fieldCode="MH" term="%22Animals%22">Animals</searchLink> ; <searchLink fieldCode="MH" term="%22Oxidative+Stress%22">Oxidative Stress</searchLink> ; <searchLink fieldCode="MH" term="%22Rats%22">Rats</searchLink> ; <searchLink fieldCode="MH" term="%22Male%22">Male</searchLink> ; <searchLink fieldCode="MH" term="%22Oxidation-Reduction%22">Oxidation-Reduction</searchLink> ; <searchLink fieldCode="MH" term="%22Apoptosis%22">Apoptosis</searchLink> ; <searchLink fieldCode="MH" term="%22Rats%2C+Sprague-Dawley%22">Rats, Sprague-Dawley</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: Background: High-altitude hypobaric hypoxia is known to impair cognitive function, but the underlying mechanistic role of impaired redox homeostasis in this context remains incompletely understood. This study investigated whether acute hypobaric hypoxia induces oxidative stress and redox dysregulation in the hippocampus, and whether oxygen enrichment can mitigate these impairments by restoring redox homeostasis.<br />Methods: Spatial memory was assessed using the Morris water maze. Additionally, hippocampal morphology, redox status (including glutathione/oxidized glutathione [GSH/GSSG], the reduced nicotinamide adenine dinucleotide/oxidized nicotinamide adenine dinucleotide [NADH/NAD+], and the reduced nicotinamide adenine dinucleotide phosphate/oxidized nicotinamide adenine dinucleotide phosphate [NADPH/NADP+] ratios, as well as antioxidant enzyme activity levels), and associated molecular pathways were analyzed.<br />Results: Following 3 days of hypoxia exposure, rats exhibited impaired spatial memory retention, increased neuronal apoptosis, and reduced neuronal viability in the hippocampal cornu ammonis 1 [CA1] region. The hippocampus displayed significantly altered redox status, characterized by elevated GSH/GSSG, NADH/NAD+, and NADPH/NADP+ ratios, upregulated antioxidant enzymes (superoxide dismutase [SOD], catalase [CAT], and glutathione peroxidase [GPX]), and decreased superoxide levels. These changes are consistent with an adaptive nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidant response and a shift toward a reductive state. Notably, oxygen enrichment rescued cognitive deficits, attenuated neuronal apoptosis, and normalized redox ratios and the microtubule-associated protein 1A/1B-light chain 3-II/microtubule-associated protein 1A/1B-light chain 3-I (LC3B-II/ LC3B-I) ratio.<br />Conclusions: Hypoxia-induced redox dysregulation is closely associated with cognitive impairment. Oxygen enrichment alleviates these deficits by modulating the Nrf2-mediated adaptive response and restoring redox homeostasis, thereby supporting further investigation of oxygen enrichment as a potential neuroprotective strategy.<br /> (Copyright: © 2026 The Author(s). Published by IMR Press.)
– Name: Abstract
  Label: Competing Interests
  Group: Ab
  Data: The authors declare no conflicts of interest. Gene Denovo Biotechnology (Guangzhou, Guangdong, China) provided technical assistance with RNA sequencing and data analysis only and had no role in the study design, interpretation of the results, preparation of the manuscript, or the decision to submit the manuscript for publication.
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  Data: 2022JQ-827 Youth Fund of the Shaanxi Province Natural Science Foundation; 2021JH053 Industry-Education-Research Innovation Fund of Chinese University
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  Label: Contributed Indexing
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  Data: <i>Keywords: </i>Nrf2; hippocampus; hypobaric hypoxia; oxygen enrichment; redox homeostasis; spatial memory
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