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Experimental Biology and Medicine 231:1576-1583 (2006)
© 2006 Society for Experimental Biology and Medicine

5TH INTERNATIONAL CONFERENCE ON METALLOTHIONEIN SYMPOSIUM PAPERS

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

Manuchair Ebadi*,1 and Sushil Sharma{dagger}

* Departments of Pharmacology and Clinical Neurosciences; and {dagger} the Center of Excellence in Neurosciences, Cyclotron and Positron Imaging Research Laboratory, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota 58202

To whom requests for reprints should be addressed at 1 University of North Dakota School of Medicine and Health Sciences, 501 North Columbia Road, Grand Forks, ND 58203. E-mail: mebadi{at}medicine.nodak.edu

Abstract

We have examined potent peroxynitrite ion (ONOO–) generator 3-morpholinosydnonimine (SIN-1)–induced neurotoxicity in control wild-type (controlwt) mice, metallothionein double knockout (MTdko) mice, metallothionein-transgenic (MTtrans) 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 18F-DOPA uptake was significantly higher in MTtrans mice than in MTdko and {alpha}-synuclein knockout ({alpha}-Synko) 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.

Key Words: metallothioneins • 3-morpholinosydnonimine • ONOO– • {alpha}-synuclein • dopamine • caspase-3 • apoptosis • transplantation • 18F-DOPA • Parkinson disease






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