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.