INDUCTION AND EXPRESSION OF BRAIN METALLOTHIONEIN

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DESCRIPTION: The long-term goal of the his project is to delineate the molecular mechanisms whereby the uneven distribution of zinc, the synthesis of zinc metallothioneins and their receptors, and the zinc- mediated events associated with synaptic events in various areas of the brain are regulated. The immediate objective of this proposal is to assess the role of zinc metallothionein in preventing the generation of oxygen radicals and oxidative damage in experimental models generating free radicals. It has been hypothesized that Parkinson's disease results from the ongoing exposure to one or more of endogenously or exogenously generated toxins, perhaps similar to 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine, with consequent free radical generation regulating in a compromised scavenging mechanism, thus causing impairment of complex I of the respiratory chain and subsequent lipid peroxidation and cell death. Electron spin resonance studies have shown that 6-hydroxydopamine generates hydroxyl radicals (OH) which is prevented by forming by selegiline and once formed is scavenged by metallothionein isoforms I and II. The specific aims of this proposal are to learn A) the effects of metallothionein in modulating the cytokine-glutathione-mediated induction of nitric oxide synthase and nitric oxide production; B) the influence of selegiline in enhancing the synthesis of metallothionein and/or superoxide dismutase and hence nullifying the neurotoxic properties of superoxide anion (OS) and/or peroxynitrite (ONOO) capable of killing striatal neurons c) the actions of metallothionein in potential the trophic effects of brain-derived neurotrophic factor in rescuing neurons against methylsalsolinol and other dopa-mediated tetrahydroisoquinoline derivatives. The information to be gained from completing these studies will contribute to understanding further the biochemical defects in dopaminergic transmission in Parkinson's disease and the neuroprotective action of metallothionein isoforms. In addition, it will explore the possibility that selegiline in addition to inhibiting monoamine oxides B, may avert neurodegeneration of striatal neurons by reducing the production of nitric oxide, superoxide anions, and peroxynitrite; and/or selegiline may foster neuroprotection by augmenting the actions of superoxide dismutase, metallothionein, or neurotrophins.