title: 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.
abstract: 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.
authors.affiliation: Neuroscience Program, University of Southern California, 90089-2520, Los Angeles, CA, USA.
authors.forename: K
authors.initials: K
authors.lastname: Pong
authors.forename: S R
authors.initials: SR
authors.lastname: Doctrow
authors.forename: M
authors.initials: M
authors.lastname: Baudry
mesh_terms: 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
chemical_list: 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