Metallothioneins 1 and 2 attenuate peroxynitrite-induced oxidative stress in Parkinson disease.
We have examined potent peroxynitrite ion (ONOO-) generator 3-morpholinosydnonimine (SIN-1)-induced neurotoxicity in control wild-type (control(wt)) mice, metallothionein double knockout (MT(dko)) mice, metallothionein-transgenic (MT(trans)) mice, and in cultured human dopaminergic (SK-N-SH) neurons to determine the neuroprotective potential of metallothionein against ONOO(-)-induced neurodegeneration in Parkinson disease (PD). SIN-1-induced lipid peroxidation, reactive oxygen species synthesis, caspase-3 activation, and apoptosis were attenuated by metallothionein gene overexpression and augmented by metallothionein gene down-regulation. A progressive nigrostriatal dopaminergic neurodegeneration in weaver mutant (wv/wv) mice was associated with enhanced nitrite ion synthesis, metallothionein down-regulation, and significantly reduced dopamine synthesis and 18F-DOPA uptake as determined by high-resolution micropositron emission tomography neuroimaging. The striatal (18)F-DOPA uptake was significantly higher in MT(trans) mice than in MT(dko) and alpha-synuclein knockout (alpha-Syn(ko)) mice. These observations provide further evidence that nitric oxide synthase activation and ONOO- synthesis may be involved in the etiopathogenesis of PD, and that metallothionein gene induction may provide neuroprotection.
Ebadi
Manuchair
M
Department of Pharmacology, University of North Dakota School of Medicine and Health Sciences, 501 North Columbia Road, Grand Forks, ND 58203, USA. mebadi@medicine.nodak.edu
Sharma
Sushil
S
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D003067:Coenzymes; D004298:Dopamine / Q000096:biosynthesis; D004789:Enzyme Activation; D015227:Lipid Peroxidation; D008668:Metallothionein / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D010300:Parkinson Disease / Q000378:metabolism / Q000503:physiopathology*; D017382:Reactive Oxygen Species; D014451:Ubiquinone / Q000031:analogs & derivatives / Q000096:biosynthesis
D003067:Coenzymes; D017382:Reactive Oxygen Species; D014451:Ubiquinone; C002385:linsidomine; D008668:Metallothionein; D008981:Molsidomine; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; C024989:coenzyme Q10; D004298:Dopamine