Cited by 82Redox biology and oxidative stressCell death mechanisms and regulationNeurological Disorders and Treatments

Developmental differences in H2O2‐induced oligodendrocyte cell death: role of glutathione, mitogen‐activated protein kinases and caspase 3

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Fragoso, Gabriela, Martínez‐Bermúdez, Ana Katherine, Liu, Hsueh‐Ning, Khorchid, Amani, Chemtob, Sylvain, Mushynski, Walter E., Almazan, Guillermina·2004·Journal of Neurochemistry

Abstract

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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  1. H 2 O 2 -induced toxicity in oligodendrocytes 403 Ó 2004 International Society for Neurochemistry, J. Neurochem. (2004) 90, 392-404 14714159, 2004, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/j.1471-4159.2004.02488.x by Mount Vernon Nazarene University, Wiley Online Library on [29/04/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License · DOI

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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
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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