The long term goal of this project is to delineate the molecular mechanisms whereby the uneven distribution of zinc, the synthesis of zinc metallothionein, and the zinc-mediated events associated with synaptic events in various areas of 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 the brain. Since many zinc containing neurons are also glutamatergic neurons, and since the mammalian hippocampus is enriched with zinc, glutamate and NMDA receptors, these studies will be carried out in hippocampal neurons in primary culture. It is hypothesized that during the inflammatory responses, the cytokine-induced induction of metallothionein provides a long lasting protection to minimize damage by oxidative stress, such as free radicals.
The specific aims of this proposal are: 1) to assess the consequence of depleting the level of glutathione by buthionine-SR- sulfoximine, of depleting the level of metallothionein by oligodeoxynucleotide, and of inducing the synthesis of metallothionein by interleukin-1 on the cytotoxicity of an organic hydroperoxide in hippocampal neurons; 2) to learn whether the induction of metallothionein by interleukin-1 can prevent the apoptotic cell death brought about by inhibition of superoxide dismutase; and 3) to ascertain whether or not the induction of and the hydroxyl radical scavenging properties of metallothionein are associated with altered activity of nitric oxide synthase. The concentrations of zinc are reduced in the brains of patients with Parkinson's disease and amyotrophic lateral sclerosis; and oxidative damage has been implicated in both conditions. The results to be gained from these studies will provide an additional insight on the role of zinc metallothionein in oxidative stress associated with these and other neurological disorders.
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