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

• Published in: Journal of neurochemistry 2004-07, Vol.90 (2), p.392-404
• Main Authors: Fragoso, Gabriela, Martínez‐Bermúdez, Ana Katherine, Liu, Hsueh‐Ning, Khorchid, Amani, Chemtob, Sylvain, Mushynski, Walter E., Almazan, Guillermina
• Format: Article
• Language: English
• Subjects: Ageing, cell death; apoptosis; Biological and medical sciences; caspases; Cell physiology; Fundamental and applied biological sciences. Psychology; Isolated neuron and nerve. Neuroglia; mitogen‐activated protein kinase; Molecular and cellular biology; N‐acetyl‐l‐cysteine; oligodendrocytes; oxidative stress; Vertebrates: nervous system and sense organs
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2004.02488.x

The molecular mechanisms underlying H2O2‐induced toxicity were characterized in rat oligodendrocyte cultures. While progenitor cells were more sensitive than mature oligodendrocytes to H2O2, 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 H2O2 stress. As free radicals have been considered to serve as second messengers, we examined the effect of H2O2 on activation of the mitogen‐activated protein kinases (MAPK), extracellular signal‐regulated kinases (ERK) 1/2 and p38. H2O2 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 H2O2 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 H2O2 toxicity in progenitors and mature oligodendrocytes. In contrast, inhibitors of both p38 and MEK reduced H2O2‐induced death most significantly in oligodendrocytes. The poly (ADP‐ribose) polymerase inhibitor, PJ34, reduced H2O2‐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.