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Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
Published on: January 30, 2014
Oxidative stress and microglial cells in Parkinson's disease
Lynda J Peterson1, Patrick M Flood
1North Carolina Oral Health Institute, The University of North Carolina at Chapel Hill, CB#7454, Chapel Hill, NC 27599-7454, USA.
Abstract:
Significant evidence has now been accumulated that microglial cells play a central role in the degeneration of DA neurons in animal models of PD. The oxidative stress response by microglial cells, most notably the activity of the enzyme NADPH oxidase, appears to play a central role in the pathology 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 p47(phox) and p67(phox) cytosolic subunits, the activation of membrane-bound PHOX, and the production of ROS. Therapeutic anti-inflammatories which prevent DA neurodegeneration in PD, 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 in microglial cells. These observations suggest a central role for the oxidative stress response in microglial cells as a mediator or regulator of DA neurodegeneration in PD.
Insights
Microglia-driven oxidative stress, particularly via NADPH oxidase, is key in Parkinson's disease (PD) neurodegeneration. Therapies targeting this pathway may prevent dopamine neuron loss in PD.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Microglial cells are increasingly recognized for their critical role in dopamine (DA) neuron degeneration observed in Parkinson's disease (PD) animal models.
- Oxidative stress, specifically mediated by NADPH oxidase activity in microglia, is a significant factor in PD pathology.
Purpose of the Study:
- To investigate the role of microglial oxidative stress in the neurodegenerative processes of Parkinson's disease.
- To explore the therapeutic potential of targeting microglial NADPH oxidase and associated inflammatory pathways.
Main Methods:
- Examined the activation of the ERK signaling pathway in microglia by proinflammatory stimuli.
- Investigated the phosphorylation and translocation of p47(phox) and p67(phox) cytosolic subunits.
- Assessed the production of reactive oxygen species (ROS) and the activation of membrane-bound PHOX.
Main Results:
- Proinflammatory stimuli activate the ERK pathway in microglia, leading to NADPH oxidase activation and ROS production.
- Therapeutic agents, including anti-inflammatory cytokines, morphinan compounds, NADPH oxidase inhibitors, NF-κB inhibitors, and β2-AR agonists, inhibit PHOX activation in microglia.
- These anti-inflammatory treatments prevent DA neurodegeneration in PD models.
Conclusions:
- Microglial oxidative stress is a central mediator and regulator of DA neurodegeneration in Parkinson's disease.
- Targeting microglial NADPH oxidase and related inflammatory signaling pathways presents a promising therapeutic strategy for PD.
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