This research has traditionally been concerned with the mechanisms of action of neurotoxins that are relatively specific for catecholamine neurons (e.g., 6-hydroxydopamine MPTP), as well as with the roles of hydrogen peroxide and reactive oxy-radicals in cellular injury. The proposed new experiments continue the theme of """"""""oxidant stress"""""""" in the nervous system in a long-range and diversified program in neurotoxicology. However, based on new findings and clues present in the literature, we focus on a new aspect of neurotoxicology: the regulation of antioxidant defense mechanisms. Although the nervous system is particularly vulnerable, it can respond positively by up-regulating oxidant defense mechanisms. To our knowledge, this fundamental topic is not under systematic investigation elsewhere. The proposed experiments utilize cell cultures of fetal rat mesencephalon and selected clonal cell lines as the main investigative tools. New findings will be verified in vivo by animal experimentation. The three interactive research aims contain components of the established study of neurotoxic mechanisms and the new focus on regulation of antioxidant mechanisms. A major goal is to further clarify the separate toxic and antioxidant properties of L-dopa (Aim 1).
In Aim 2 we will systematically monitor and document up-regulation of antioxidant defenses by growth factors or by prior exposure to an oxidant stress. Subsequently, changes in cellular vulnerability after up-regulation of oxidant defenses will be studied.
In Aim 3, mechanistic aspects of neurotoxicity will be further clarified. Portions of the work relate directly to the treatment of Parkinson patients with L-dopa. The regulation of defense mechanisms, and/or its failure, undoubtedly play prominent roles in responses to neurotoxins, and in natural processes associated with aging of the CNS and neurodegenerative diseases (e.g., Parkinson's, Alzheimer's).
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