Catecholamine-induced oligodendrocyte cell death in culture is developmentally regulated and involves free radical generation and differential activation of caspase-3.
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.
Khorchid
Amani
A
Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.
Fragoso
Gabriela
G
Shore
Gordon
G
Almazan
Guillermina
G
D000111:Acetylcysteine / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001238:Asphyxia Neonatorum / Q000201:enzymology / Q000503:physiopathology; D001921:Brain / Q000201:enzymology / Q000254:growth & development* / Q000503:physiopathology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002395:Catecholamines / Q000378:metabolism / Q000633:toxicity*; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005609:Free Radicals / Q000378:metabolism; D019254:Genes, bcl-2 / Q000235:genetics; D005978:Glutathione / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D051547:Heme Oxygenase-1; D006801:Humans; D007231:Infant, Newborn; D007969:Leukomalacia, Periventricular / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology; D008565:Membrane Proteins; D009836:Oligodendroglia / Q000187:drug effects / Q000201:enzymology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013234:Stem Cells / Q000187:drug effects / Q000201:enzymology*
D002395:Catecholamines; D004791:Enzyme Inhibitors; D005609:Free Radicals; D008565:Membrane Proteins; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D011065:Poly(ADP-ribose) Polymerases; C505407:CASP3 protein, human; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D005978:Glutathione; D000111:Acetylcysteine