Metallothioneins 1 and 2 Attenuate Peroxynitrite-Induced Oxidative Stress in Parkinson Disease

Abstract

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 neurodegeneratlon 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 ¹⁸F-DOPA uptake was significantly higher in MT_trans mice than in MT_dko and α-synuclein knockout (α-Syn_ko) mice. These observations provide further evidence that nitric oxide synthase activation and ONOO^- synthesis may be involved in the etiopathogenesls of PD, and that metallothionein gene induction may provide neuroprotection.