Hydrogen peroxide (H2O2) is a neurotoxic agent that is generated during the natural oxidation of dopamine (DA) by monoamine oxidase (MAO). H202 is detoxified mainly by glutathione peroxidase (GSH-Px), which produces glutathione disulfide (GSSG). Under normal circumstances, GSSG does not accumulate because it is effectively reduced by GSSG reductase. When GSSG does accumulate, it serves as an indicator of an """"""""oxidative stress"""""""". Studies by others with non-neural tissues have shown that accumulation of GSSG is associated with toxic events. During aging, and specifically in Parkinson's disease, surviving nigrostriatal neurons exhibit increased turnover of DA; hence, both aging and Parkinson's disease are characterized by a self-generated oxidative stress, derived from the increased rate of production of H202. We have shown that increased DA turnover in rodents elevates GSSG in the striatum. This observation provides a definitive marker of oxidant stress and unlocks the study of oxidative events at dopaminergic synapses. Primary goals of the research proposal are to study in detail the extent and course of oxidative changes (pharmacokinetics) during exposure to drugs that alter DA turnover (Aim 1) and to assess gene expression and regulation of GSH-PX (mRNA and enzyme protein) in DA neurons (Aim 2). Preliminary data are available for key experimental approaches in these areas. The studies also include autopsy specimens of human brain and oxidative changes in monkey brain (Aim 3). Long range goals (Aim 4) encompass effects of enhanced DA turnover on SH-dependent enzymes and proteins, and assessment of gene expression for GSSG reductase. These studies open a new vista into the central nervous system. At a basic level, they will provide fundamental information about the dynamics of the critical glutathione status (GSSG, GSH, protein mixed-disulfides) at dopaminergic synapses, as well as the distribution and regulation of GSH-Px and GSSG reductase in brain. In practical terms, the studies should prove valuable for understanding Parkinson's disease as well as for designing new strategies for treatment. The results reflect immediately on the clinical use of deprenyl (inhibitor of MAO-B) in the treatment of Parkinson's disease. Over the long range, the developing concepts and results should also impact upon other areas where oxidative stress is implicated in the CNS, such as aging, reperfusion injury after stroke, and Alzheimer's disease.
| Werner, P; Cohen, G (1993) Glutathione disulfide (GSSG) as a marker of oxidative injury to brain mitochondria. Ann N Y Acad Sci 679:364-9 |
