Deficient peroxide detoxification underlies the susceptibility of oligodendrocyte progenitors to dopamine toxicity.
Oligodendrocyte progenitors are highly susceptible to oxidative stress due to their limited content of antioxidants and high iron levels. We previously showed that iron plays a central role in the toxicity of dopamine (DA) to oligodendrocyte progenitors. Here, we further explore the mechanisms involved in DA toxicity, specifically the role of superoxide and the glutathione system. DA induces accumulation of superoxide, membrane damage and loss in cell viability. An iron chelator, deferoxamine, reduces superoxide accumulation. However, a superoxide dismutase mimetic, MnTBAP, potentiates DA toxicity, suggesting that superoxide plays an indirect role in toxicity through dismutation to H2O2. In addition, the glutathione (GSH) analog (GME), blocks DA-induced superoxide accumulation, heme-oxygenase-1 (HO-1) expression and caspase-3 activation, and reduces cell death, while the glutathione synthetase inhibitor, buthionine sulfoximine, potentiates DA-induced HO-1 expression and cell death. Moreover, a mimetic of the peroxide-scavenging enzyme, glutathione peroxidase (GPx), ebselen, blocks caspase-3 activation induced by DA alone or in combination with iron. In conclusion, superoxide and inadequate defense by glutathione and GPx are responsible for the susceptibility of oligodendrocyte progenitors to DA toxicity. Furthermore, peroxides play a primary role in toxicity induced by DA and iron.
Hemdan
Sandy
S
Department of Pharmacology and Therapeutics, McGill University, 3655 Promenade Sir William Osler, Room 1321, Montreal, QC H3G 1Y6, Canada.
Almazan
Guillermina
G
D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000494:pharmacology; D001393:Azoles / Q000494:pharmacology; D015153:Blotting, Western; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002478:Cells, Cultured; D004298:Dopamine / Q000633:toxicity*; D005978:Glutathione / Q000502:physiology; D051547:Heme Oxygenase-1 / Q000096:biosynthesis; D007501:Iron / Q000494:pharmacology; D054833:Isoindoles; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008665:Metalloporphyrins / Q000494:pharmacology; D009836:Oligodendroglia / Q000187:drug effects* / Q000378:metabolism*; D016566:Organoselenium Compounds / Q000494:pharmacology; D016877:Oxidants / Q000378:metabolism* / Q000633:toxicity; D010545:Peroxides / Q000378:metabolism* / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013234:Stem Cells / Q000187:drug effects* / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D013778:Tetrazolium Salts; D013844:Thiazoles
D000975:Antioxidants; D001393:Azoles; D054833:Isoindoles; D008665:Metalloporphyrins; D016566:Organoselenium Compounds; D016877:Oxidants; D010545:Peroxides; D017382:Reactive Oxygen Species; D013778:Tetrazolium Salts; D013844:Thiazoles; C097284:manganese(III)-tetrakis(4-benzoic acid)porphyrin; D013481:Superoxides; C042986:ebselen; D019328:Buthionine Sulfoximine; D007501:Iron; D007770:L-Lactate Dehydrogenase; D051547:Heme Oxygenase-1; D013482:Superoxide Dismutase; C022616:thiazolyl blue; D005978:Glutathione; D004298:Dopamine