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Cited by 292Stress Responses and CortisolRedox biology and oxidative stressAdrenal Hormones and Disorders

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Activation of the hypothalamic-pituitary-adrenal stress axis induces cellular oxidative stress

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Spiers, Jereme G., Chen, Hsiao-Jou Cortina, Sernia, Conrad, Lavidis, Nickolas A.·2015·Frontiers in Neuroscience
DOI 10.3389/fnins.2014.00456PMC PMC4298223
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Abstract

Glucocorticoids released from the adrenal gland in response to stress-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis induce activity in the cellular reduction-oxidation (redox) system. The redox system is a ubiquitous chemical mechanism allowing the transfer of electrons between donor/acceptors and target molecules during oxidative phosphorylation while simultaneously maintaining the overall cellular environment in a reduced state. The objective of this review is to present an overview of the current literature discussing the link between HPA axis-derived glucocorticoids and increased oxidative stress, particularly focussing on the redox changes observed in the hippocampus following glucocorticoid exposure.

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Crossref · 10.3389/fnins.2014.00456

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Figure 1 Schematic representation of neural redox reactions. Stress causes an increase in corticosterone which activates cytosolic glucocorticoid receptors (GR). These translocate into the nucleus to modulate gene transcription through glucocorticoid responsive elements (GRE), or co-localize with the anti-apoptotic Bcl-2 protein and translocate into the mitochondria. This increases mitochondrial membrane potential, calcium holding capacity, and mitochondrial oxidation. The increase in cellular metabolic rate promotes ATP synthesis in addition to spontaneous superoxide (O−2) production via complex I and III of the electron transport chain. This is dismutated to hydrogen peroxide (H2O2) by manganese superoxide dismutase (Mn-SOD) and can be further converted to hydroxyl radical (OH−) or reduced to water by the mitochondrial antioxidant pathway. In the cytosol, a major source of superoxide production is via the oxidation of NADPH via NADPH oxidase. Cytosolic superoxide is dismutated to hydrogen peroxide by copper, zinc-superoxide dismutase (Cu, Zn-SOD). Hydrogen peroxide is neutralized by catalase (CAT) or glutathione peroxidase (GPx) which oxidizes the reduced form of glutathione (GSH) to oxidized glutathione (GSSG). GSH is then regenerated from GSSG via the glutathione reductase (GSR) enzymatic system. Hydrogen peroxide can also interact with superoxide radicals and/or transition metals such as Fe2+ or Cu2+ to produce the highly toxic hydroxyl radical by Haber-Weiss and Fenton chemistry. An increase in the production of superoxide, hydrogen peroxide, and hydroxyl radicals leads to a state of cellular oxidative stress which causes oxidative damage to DNA, protein carbonyl formation, and membrane lipid peroxidation (LPO). Hydrogen peroxide is membrane permeable and moves freely from mitochondrial to cytosolic compartments, in addition to traversing the extracellular space to affect neighboring neurons and glial cells. Superoxide radicals can also induce oxidative stress in neighboring cells by diffusing through membrane-bound anion channels. The majority of neuronal and astrocytic reactive oxygen species are produced by mitochondrial oxidation, while other cell types such as microglia rely heavily on the cytosolic NADPH-oxidase system to produce a respiratory burst in response to invading pathogens. However, in comparison to glial cells, neurons display a relatively poor expression of endogenous antioxidants, making them more vulnerable to oxidative stress.
Figure 1 Schematic representation of neural redox reactions. Stress causes an increase in corticosterone which activates cytosolic glucocorticoid receptors (GR). These translocate into the nucleus to modulate gene transcription through glucocorticoid responsive elements (GRE), or co-localize with the anti-apoptotic Bcl-2 protein and translocate into the mitochondria. This increases mitochondrial membrane potential, calcium holding capacity, and mitochondrial oxidation. The increase in cellular metabolic rate promotes ATP synthesis in addition to spontaneous superoxide (O−2) production via complex I and III of the electron transport chain. This is dismutated to hydrogen peroxide (H2O2) by manganese superoxide dismutase (Mn-SOD) and can be further converted to hydroxyl radical (OH−) or reduced to water by the mitochondrial antioxidant pathway. In the cytosol, a major source of superoxide production is via the oxidation of NADPH via NADPH oxidase. Cytosolic superoxide is dismutated to hydrogen peroxide by copper, zinc-superoxide dismutase (Cu, Zn-SOD). Hydrogen peroxide is neutralized by catalase (CAT) or glutathione peroxidase (GPx) which oxidizes the reduced form of glutathione (GSH) to oxidized glutathione (GSSG). GSH is then regenerated from GSSG via the glutathione reductase (GSR) enzymatic system. Hydrogen peroxide can also interact with superoxide radicals and/or transition metals such as Fe2+ or Cu2+ to produce the highly toxic hydroxyl radical by Haber-Weiss and Fenton chemistry. An increase in the production of superoxide, hydrogen peroxide, and hydroxyl radicals leads to a state of cellular oxidative stress which causes oxidative damage to DNA, protein carbonyl formation, and membrane lipid peroxidation (LPO). Hydrogen peroxide is membrane permeable and moves freely from mitochondrial to cytosolic compartments, in addition to traversing the extracellular space to affect neighboring neurons and glial cells. Superoxide radicals can also induce oxidative stress in neighboring cells by diffusing through membrane-bound anion channels. The majority of neuronal and astrocytic reactive oxygen species are produced by mitochondrial oxidation, while other cell types such as microglia rely heavily on the cytosolic NADPH-oxidase system to produce a respiratory burst in response to invading pathogens. However, in comparison to glial cells, neurons display a relatively poor expression of endogenous antioxidants, making them more vulnerable to oxidative stress.CC BY · PubMed Central

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Research works printed but not linked: 3

  1. Barycki, 2007, Antioxidant Molecules and Redox Cofactors, Redox Biochemistry
  2. Fridovich, 2007, Antioxidant Enzymes, Redox Biochemistry
  3. Rovira, 2007, Redox Regulation of Physiological Processes, Redox Biochemistry

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Metadata

Authors
Spiers, J. G., Chen, H.-J. C., Sernia, C., & Lavidis, N. A.
Affiliations
The University of Queensland (AU)
Corresponding author
Spiers, Jereme G.
ORCID
Venue
Frontiers in Neuroscience
Publisher
Frontiers Media SA
Published
2015-01-19
Volume
8
Pages
456-456
ISSN
1662-453X (ISSN-L)
DOI
10.3389/fnins.2014.00456
PMC
PMC4298223
OpenAlex
W1984410984
Cited by
292
References
73
Citations by year
2026: 24 · 2025: 39 · 2024: 23 · 2023: 33 · 2022: 30 · 2021: 39 · 2020: 29 · 2019: 21 · 2018: 17 · 2017: 20 · 2016: 11 · 2015: 6
FWCI
1.45
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Frontiers in Neuroscience (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Topics
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
Keywords
hypothalamic-pituitary-adrenal axis, glucocorticoids, oxidative stress, redox systems, hippocampus, stress, adrenal cortex, neuroendocrinology

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