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Developmental differences in HO-induced oligodendrocyte cell death: role of glutathione, mitogen-activated protein kinases and caspase 3.
J Neurochem. 2004 Jul; 90(2):392-404.JN

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.

Authors+Show Affiliations

Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15228596

Citation

Fragoso, Gabriela, et al. "Developmental Differences in HO-induced Oligodendrocyte Cell Death: Role of Glutathione, Mitogen-activated Protein Kinases and Caspase 3." Journal of Neurochemistry, vol. 90, no. 2, 2004, pp. 392-404.
Fragoso G, Martínez-Bermúdez AK, Liu HN, et al. Developmental differences in HO-induced oligodendrocyte cell death: role of glutathione, mitogen-activated protein kinases and caspase 3. J Neurochem. 2004;90(2):392-404.
Fragoso, G., Martínez-Bermúdez, A. K., Liu, H. N., Khorchid, A., Chemtob, S., Mushynski, W. E., & Almazan, G. (2004). Developmental differences in HO-induced oligodendrocyte cell death: role of glutathione, mitogen-activated protein kinases and caspase 3. Journal of Neurochemistry, 90(2), 392-404.
Fragoso G, et al. Developmental Differences in HO-induced Oligodendrocyte Cell Death: Role of Glutathione, Mitogen-activated Protein Kinases and Caspase 3. J Neurochem. 2004;90(2):392-404. PubMed PMID: 15228596.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Developmental differences in HO-induced oligodendrocyte cell death: role of glutathione, mitogen-activated protein kinases and caspase 3. AU - Fragoso,Gabriela, AU - Martínez-Bermúdez,Ana Katherine, AU - Liu,Hsueh-Ning, AU - Khorchid,Amani, AU - Chemtob,Sylvain, AU - Mushynski,Walter E, AU - Almazan,Guillermina, PY - 2004/7/2/pubmed PY - 2004/9/4/medline PY - 2004/7/2/entrez SP - 392 EP - 404 JF - Journal of neurochemistry JO - J Neurochem VL - 90 IS - 2 N2 - 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. SN - 0022-3042 UR - https://www.unboundmedicine.com/medline/citation/15228596/Developmental_differences_in_HO_induced_oligodendrocyte_cell_death:_role_of_glutathione_mitogen_activated_protein_kinases_and_caspase_3_ L2 - https://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0022-3042&date=2004&volume=90&issue=2&spage=392 DB - PRIME DP - Unbound Medicine ER -