Oxidative stress is an important causative factor in the onset and maintenance of several neurodegenerative conditions, such as Alzheimer's disease and Parkinson's Disease (PD). While dopamine (DA)-replacement therapy can control the symptoms of PD, it can also cause severe dyskinesia in patients. Blockage of the D1 DA receptors with Dl-selective antagonists in 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP)-lesioned primates, significantly improves dyskinesia, through unknown mechanisms. Autoxidation of DA is a major source of free radicals; activation of D1 receptors also triggers oxidative stress, and these effects are additive, such that the resulting damage produced in the postsynaptic cell is several fold greater than that elicited by sources of free radicals (hydrogen peroxide (H202)), which does not stimulate the D1 receptor. Several indices of oxidative stress, lipid peroxidation, nitrite production, nitric oxide synthases, neurofilament (NF)-kappaB nuclear translocation, are all elevated two to six fold higher with DA-mediated D1 receptor activation, than H202 alone. We will examine in detail the contribution of D1 receptor stimulation, through the use of agonists and antagonists, in causing oxidative stress in SK-N-MC human neuroblastoma cells, which endogenously express the D1 receptor and is representative of postsynaptic cells. We will examine the mechanism and functional consequences of D1 receptor stimulation on signaling pathways, as well as by selectively blocking parts of the oxidative stress cascade(s). The participation of D1 receptors and oxidative stress in cell death and apoptosis will also be measured. Since blockage of D1 receptors in the MPTP model of PD improves some of the symptoms of PD, we will investigate whether D1 receptors augment MPTP effects in SK-N-MC cells. Conversely, blockage of D1 receptors with antagonists may attenuate MPTP effects on the various indices of oxidative stress. A clear understanding of the effects of dopamine autoxidation and the participation of D1 DA receptors in inducing oxidative stress, is important for understanding patient response to agonist therapy in PD, and may aid in the design of novel therapeutic treatments.
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