Iron contributes to dopamine-induced toxicity in oligodendrocyte progenitors.
Iron is potentially toxic to oligodendrocyte progenitors due to its high intracellular levels and its ability to catalyse oxidant-producing reactions. Oxidative stress resulting from a hypoxic-ischaemic insult has been implicated in death of oligodendrocyte progenitors that occurs in the hypomyelinating disorder periventricular leucomalacia. Ischaemic insults induce the release of various neurotransmitters, including dopamine (DA), and we previously showed that DA is toxic to cultured oligodendrocytes, by inducing oxidative stress and apoptosis. Therefore, we investigated the role of iron in DA-induced cell death in oligodendrocyte progenitors. Intracellular iron levels were altered using an iron chelator, deferoxamine (DFO), and supplementation with ferrous sulphate (FeSO(4)). Addition of FeSO(4) to cultures increased DA-induced toxicity as assessed by mitochondrial dehydrogenase activity and cellular release of lactate dehydrogenase. Furthermore, FeSO(4) increased expression of the stress protein heme oxygenase-1 (HO-1), nuclear condensation and caspase-3 activation. In contrast, preincubation with DFO reduced these events as well as cleavage of alpha-spectrin, a caspase-3 substrate. In addition, FeSO(4) reversed the protective effect of DFO on DA-induced cytotoxicity, HO-1 expression and caspase-3 activation. These results indicate that elevated levels of free iron contribute to DA-induced toxicity in oligodendrocyte progenitors.
Hemdan
S
S
Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.
Almazan
G
G
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D053148:Caspase 3; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects; D003676:Deferoxamine / Q000494:pharmacology; D004298:Dopamine / Q000633:toxicity*; D015259:Dopamine Agents / Q000633:toxicity*; D004789:Enzyme Activation / Q000187:drug effects; D005296:Ferrous Compounds / Q000378:metabolism / Q000633:toxicity*; D051547:Heme Oxygenase-1 / Q000187:drug effects; D009336:Necrosis; D009836:Oligodendroglia / Q000187:drug effects* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017262:Siderophores / Q000494:pharmacology; D013234:Stem Cells / Q000187:drug effects* / Q000473:pathology
D015259:Dopamine Agents; D005296:Ferrous Compounds; D017262:Siderophores; C020748:ferrous sulfate; D051547:Heme Oxygenase-1; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D003676:Deferoxamine; D004298:Dopamine