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Levodopa-induced motor complications remain an important source of disability for many patients with Parkinson's disease. Substantial laboratory evidence indicates that motor complications relate to the nonphysiological restoration of brain dopamine with intermittent doses of standard oral levodopa. Dopamine levels are normally maintained at a relatively constant level, even following a dose of levodopa. However, in the Parkinsonian state, where dopamine terminals have degenerated with a loss of their buffering capacity, intermittent doses of levodopa lead to dramatic peak and trough fluctuations in striatal dopamine levels. This results in pulsatile stimulation of dopamine receptors, molecular changes in striatal neurons, physiological changes in pallidal neurons, and ultimately the development of motor complications. These observations led to the hypothesis that continuous delivery of levodopa might be associated with a reduced risk of motor complications. This concept is known as continuous dopamine stimulation (CDS). Preliminary studies in animal models and patients with Parkinson's disease supported this hypothesis, suggesting a reduced risk of both motor fluctuations and dyskinesias. The present review considers the scientific advances and the more definitive clinical trials testing this concept that have taken place during the past decade and considers ongoing experimental studies and future opportunities. © 2020 International Parkinson and Movement Disorder Society.

Parkinson's disease is characterized by the depletion of glutathione (GSH) in, the substantia nigra and the degeneration of nigral dopamine neurons. In our stud: we examined the relationship between cellular GSH depletion and neuronal degeneration. Using rat mesencephalic cultures as a model, we found that GSH depletion results in phospholipase A, (PLA(sub 2))-dependent release of arachidonic acid and increase in lipoxygenase (LOX-dependent arachidonic acid metabolism. These events generate reactive oxygen species, which accumulate in the cells and result in oxidative stress and cell death. Cell death can be prevented by interrupting different steps of this process, including replenishment of GSH, inhibition of PLA_ activity, inhibition of LOX activity and increase in the antioxidant defenses of the cells (up-regulation of superoxide dismutase, addition of ascorbic acid). Our studies provide information, which may be important in the understanding of the etiology of Parkinson's disease and could offer insights for the design of medication to prevent the progress of the disorder in Parkinson's patients., All DTIC reproductions will be in black and white. Original contains color plates

The experiments performed during the third grant period were an extension of the 2nd year and were designed to provide more insights in the role of arachidonic acid release and metabolism in the oxidative stress-induced cell death caused by depletion of GSH. In addition we examined the time course of free radical generation in cells depleted of GSH. Our studies using primary mesencephalic cultures provided the following information. (l) Using selective inhibitors we showed that the release of arachidonic acid occurs early in the period of GSH depletion and depends on the activation of PLA2. (2) We showed that inhibition of PLA2 activity protects fully from damage only if applied early in the course of GSH depletion, while inhibition of arachidonic acid metabolism is protective at any time prior to cell death. This suggests that products of the metabolism of arachidonic acid are the major cause of toxicity. (3) We confirmed that products of arachidonic acid metabolism are very toxic particularly when GSH is depleted. (3) We demonstrated that hydrogen peroxide and other reactive oxygen species (ROS) accumulate in detectable amounts only a few hours prior to cell death. Accumulation begins within mitochondria and later involves processes and cell bodies. Anti-oxidants are protective when applied anytime following damage., Original contains color plates: All DTIC reproductions will be in black and white.