Developmental differences in H2O2‐induced oligodendrocyte cell death: role of glutathione, mitogen‐activated protein kinases and caspase 3
Open accessAbstract
The molecular mechanisms underlying H(2)O(2)-induced toxicity were characterized in rat oligodendrocyte cultures. While progenitor cells were more sensitive than mature oligodendrocytes to H(2)O(2), the antioxidant, N-acetyl-L-cysteine, blocked toxicity at both stages of development. Differentiated oligodendrocytes contained more glutathione than did progenitors and were less susceptible to decreases in glutathione concentration induced by H(2)O(2) stress. As free radicals have been considered to serve as second messengers, we examined the effect of H(2)O(2) on activation of the mitogen-activated protein kinases (MAPK), extracellular signal-regulated kinases (ERK) 1/2 and p38. H(2)O(2) caused a time- and concentration-dependent increase in MAPK phosphorylation, an effect that was totally blocked by N-acetyl-L-cysteine. Further exploration of potential mechanisms involved in oligodendrocyte cell death showed that H(2)O(2) treatment caused DNA condensation and fragmentation at both stages of development, whereas caspase 3 activation and poly (ADP-ribose) polymerase cleavage were significantly increased only in oligodendrocyte progenitors. The pan-caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp fluoromethyl ketone, blocked DNA fragmentation in progenitors and produced a small but significant level of protection from H(2)O(2) toxicity in progenitors and mature oligodendrocytes. In contrast, inhibitors of both p38 and MEK reduced H(2)O(2)-induced death most significantly in oligodendrocytes. The poly (ADP-ribose) polymerase inhibitor, PJ34, reduced H(2)O(2)-induced toxicity on its own but was most effective when combined with benzyloxycarbonyl-Val-Ala-Asp fluoromethyl ketone or PD169316. The finding that molecular mechanisms conferring resistance to reactive oxygen species toxicity are regulated during oligodendrocyte differentiation may be of importance in designing therapies for certain neurological diseases affecting white matter.
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In vitro studies show that oligodendrocytes are susceptible to oxidative stress because of their high metabolic activity and iron content combined with low antioxidant levels.
“In vitro studies show that oligodendrocytes are susceptible to oxidative stress due to their high metabolic activity and iron content combined with low antioxidant levels (Back et al., 1998; Baud et al., 2004; Fragoso et al., 2004).”
From Redox dysregulation, neuroinflammation, and NMDA receptor hypofunction: A “central hub” in schizophrenia pathophysiology? (2016) · cites this paper as Fragoso et al., 2004
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Molecular mechanisms involved in oligodendrocyte development
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- Authors
- Fragoso, G., Martínez‐Bermúdez, A. K., Liu, H., Khorchid, A., Chemtob, S., Mushynski, W. E., & Almazan, G.
- Affiliations
- McGill University (CA)
- Centre Hospitalier Universitaire Sainte-Justine (CA)
- Venue
- Journal of Neurochemistry
- Publisher
- Wiley
- Published
- 2004-06-10
- Volume
- 90
- Issue
- 2
- Pages
- 392-404
- ISSN
- 0022-3042 (ISSN-L)
- 1471-4159
- OpenAlex
- W2086736202
- Cited by
- 82
- References
- 64
- Citations by year
- 2025: 1 · 2024: 2 · 2022: 2 · 2021: 2 · 2020: 5 · 2019: 4 · 2018: 2 · 2017: 6 · 2016: 3 · 2015: 4 · 2014: 3 · 2013: 4 · 2012: 1
- FWCI
- 2.96
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neurochemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Multiple Sclerosis Society of Canada
- Canadian Institutes of Health Research
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Neuroscience › Neurology › Neurological Disorders and Treatments
- Keywords
- hydrogen peroxide toxicity, oligodendrocyte cell death, oligodendrocyte differentiation, oligodendrocyte progenitors, glutathione, N-acetylcysteine, reactive oxygen species, mitogen-activated protein kinase, ERK1/2, p38 MAPK, caspase-3, poly(ADP-ribose) polymerase, DNA fragmentation, PD169316, white matter disease
- MeSH terms
- Poly(ADP-ribose) Polymerase Inhibitors, Acetylcysteine, Animals, Antioxidants, Cell Survival, Cells, Cultured, Dose-Response Relationship, Drug, Enzyme Activation, Enzyme Inhibitors, Glutathione, Hydrogen Peroxide, Necrosis, Oligodendroglia, Stem Cells, Oxidants, Cell Death, Apoptosis, Oxidative Stress, Caspases, Mitogen-Activated Protein Kinases, Rats, Caspase 3
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