Prevention of 1-methyl-4-phenylpyridinium- and 6-hydroxydopamine-induced nitration of tyrosine hydroxylase and neurotoxicity by EUK-134, a superoxide dismutase and catalase mimetic, in cultured dopaminergic neurons.
Oxidative stress has been implicated in the selective degeneration of dopaminergic (DAergic) neurons in Parkinson's disease (PD). In this study, we tested the efficacy of EUK-134, a superoxide dismutase (SOD) and catalase mimetic, on the nitration of tyrosine hydroxylase (TH), a marker of oxidative stress, and neurotoxicity produced by 1-methyl-4-phenylpyridinium (MPP(+)) and 6-hydroxydopamine (6-OHDA) in primary DAergic neuron cultures. Exposure of cultures to 10 microM MPP(+) reduced dopamine (DA) uptake and the number of tyrosine hydroxylase immunoreactive (THir) neurons to 56 and 52% of control, while exposure to 30 microM 6-OHDA reduced DA uptake and the number of THir neurons to 58 and 59% of control, respectively. Pretreatment of cultures with 0.5 microM EUK-134 completely protected DAergic neurons against MPP(+)- and 6-OHDA-induced neurotoxicity. Exposure of primary neuron cultures to either MPP(+) or 6-OHDA produced nitration of tyrosine residues in TH. Pretreatment of cultures with 0.5 microM EUK-134 completely prevented MPP(+)- or 6-OHDA-induced nitration of tyrosine residues in TH. Taken together, these results support the idea that reactive oxygen species (ROS) are critically involved in MPP(+)- and 6-OHDA-induced neurotoxicity and suggest a potential therapeutic role for synthetic catalytic scavengers of ROS, such as EUK-134, in the treatment of PD.
Pong
K
K
Neuroscience Program, University of Southern California, 90089-2520, Los Angeles, CA, USA.
Doctrow
S R
SR
Baudry
M
M
D015655:1-Methyl-4-phenylpyridinium / Q000037:antagonists & inhibitors / Q000494:pharmacology; D018663:Adrenergic Agents / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism*; D004622:Embryo, Mammalian; D005029:Ethylenediamines / Q000494:pharmacology*; D016166:Free Radical Scavengers / Q000494:pharmacology*; D006540:Herbicides / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009942:Organometallic Compounds / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D016627:Oxidopamine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000494:pharmacology*; D014446:Tyrosine 3-Monooxygenase / Q000187:drug effects* / Q000378:metabolism
D018663:Adrenergic Agents; D005029:Ethylenediamines; D016166:Free Radical Scavengers; D006540:Herbicides; D018696:Neuroprotective Agents; D009942:Organometallic Compounds; C090577:N,N'-bis(salicylideneamino)ethane-manganese(II); D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D013482:Superoxide Dismutase; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine