Oxidative Stress and Microglial Cells in Parkinson's Disease
Figure 2
Chronic production of inflammatory mediators by microglial cells, particularly the generation of ROS and NO by activated microglia, mediates the majority of DA-neuronal degeneration and cell death. As resident brain macrophages, microglia continually survey the surrounding tissue where they remain in an inactive, quiescent state under tight regulation such as by the interaction of cell-surface molecules CD200 (expressed on neurons) and CD200R receptor on the microglia. Microglia become activated when they encounter extracellular triggers such as those from the pathogens, structurally or genetically altered proteins, toxins, and dead or dying neuronal cells. Activated microglia generate a strong proinflammatory response including the production of inflammatory cytokines (e.g., TNFα, IL-6, IL-1β) and an oxidative stress response. Most notably, the activity of the oxidative-stress enzyme, NADPH oxidase, appears to play a central role in the pathology of DA-neuron death and the progression of PD. This oxidative stress response occurs in microglia through the activation of the ERK signaling pathway by proinflammatory stimuli, leading to the phosphorylation and translocation of the p47phox and p67phox cytosolic subunits, the activation of membrane-bound PHOX, and the production of ROS. Therapeutic anti-inflammatories which prevent DA neurodegeneration in PD models, including anti-inflammatory cytokines, morphinan compounds, NADPH oxidase inhibitors, NF-κB inhibitors, and β2-AR agonists, all function to inhibit the activation of the PHOX complex and ROS production in microglial cells.
