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Catecholamine‐induced oligodendrocyte cell death in culture is developmentally regulated and involves free radical generation and differential activation of caspase‐3
Author(s) -
Khorchid Amani,
Fragoso Gabriela,
Shore Gordon,
Almazan Guillermina
Publication year - 2002
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.10123
Subject(s) - oligodendrocyte , biology , programmed cell death , oxidative stress , apoptosis , caspase , microbiology and biotechnology , caspase 3 , progenitor cell , dna fragmentation , glutathione , biochemistry , endocrinology , stem cell , myelin , central nervous system , enzyme
Oligodendrocyte cultures were used to study the toxic effects of catecholamines. Our results showed that catecholamine‐induced toxicity was dependent on the dose of dopamine or norepinephrine used and on the developmental stage of the cultures, with oligodendrocyte progenitors being more vulnerable. A role for oxidative stress and apoptosis on the mechanism of action of catecholamines on oligodendrocyte cell death was next assessed. Catecholamines caused a reduction in intracellular glutathione levels, an accumulation in reactive oxygen species and in heme oxygenase‐1, the 32 kDa stress‐induced protein. All these changes were prevented by N‐acetyl‐L‐cysteine, a thiocompound with antioxidant activity and a precursor of glutathione, and were more pronounced in progenitors than mature cells, which could contribute to their higher susceptibility. Apoptotic cell death, as assessed by activation of caspase‐9 and –3 and cleavage of poly(ADP‐ribose) polymerase (a substrate of caspase‐3), was only observed in oligodendrocyte progenitors. Pretreatment with zVAD, a general caspase inhibitor, prevented activation of caspase‐9 and ‐3, DNA fragmentation, and decreased progenitors cell death. Furthermore, the expression levels of procaspase‐3 and the ratio of the proapoptotic protein bax to antiapoptotic protein bcl‐xl were several folds higher in immature than mature oligodendrocytes. Taken together, these results strongly suggest that the catecholamine‐induced cytotoxicity in oligodendrocytes is developmentally regulated, mediated by oxidative stress, and have characteristics of apoptosis in progenitor cells. GLIA 40:283–299, 2002. © 2002 Wiley‐Liss, Inc.