Inflammatory Response and Oxidative Stress in the Degeneration of Dopamine Neurons in Parkinson's Disease

摘要

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.