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Are Temporal Differences in GDNF and NOS Isoform Induction Contributors to Neurodegeneration? A Fluorescence
Marie-Francoise Doursout1, Yangyan Liang1, Mya C Schiess2
1Department of Anesthesiology, University of Texas McGovern Medical School, Houston,Texas, USA.
Background:
Specific factors in Parkinson's disease have become targets as to their protective and degenerative effects. We have demonstrated that cytokines and PD-CSF detrimentally affect microglia and astrocyte growth. While glial cell-derived neurotrophic factor (GDNF) has been recognized as a possible neuron-rescue agent, nitric oxide synthase (NOS) has been implicated in neurodegenerative processes.
Objective:
To demonstrate that glial cell activation, cytokine production, and NOS induction, play an intimate role in the loss of dopaminergic signaling, via mechanisms that are a result of inflammation and inflammatory stimuli.
Methods:
Study animals were sacrificed following endotoxin treatment and tissue sections were harvested and probed for GDNF and NOS isomers by fluorescence deconvolution microscopy. Fluorescence was mapped and quantified for each probe.
Results:
An immune cell influx into 'vulnerable' areas of the brain was seen, and three NOS isomers, inducible (iNOS), neuronal (nNOS) and endothelial (eNOS), were synthesized in the brains, a finding which suggests that each isomer has a role in neurodegeneration. eNOS was found associated with blood vessels, while iNOS was associated with glial and matrix cells and nNOS was located with both glia and neurons. Following endotoxin treatment, serum levels of nitric oxide were higher at 6-8 hours, while tissue levels of NOS were elevated for much longer. Thus, induction of NOS occurred earlier than the induction of GDNF.
Conclusion:
Our findings suggest that the protective abilities of GDNF to combat neural destruction are not available rapidly enough, and do not remain at sufficiently high levels long enough to assert its protective effects. (250).
Insights
Glial cell activation and nitric oxide synthase (NOS) induction contribute to dopaminergic neuron loss in Parkinson's disease. Glial cell-derived neurotrophic factor (GDNF) is not produced quickly or abundantly enough to prevent this neurodegeneration.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Cytokines and PD-CSF negatively impact microglia and astrocyte growth.
- Glial cell-derived neurotrophic factor (GDNF) shows potential for neuron rescue.
- Nitric oxide synthase (NOS) is implicated in neurodegenerative processes.
Purpose of the Study:
- To demonstrate the role of glial cell activation, cytokine production, and NOS induction in dopaminergic signaling loss.
- To elucidate mechanisms involving inflammation and inflammatory stimuli in Parkinson's disease pathogenesis.
Main Methods:
- Animals were treated with endotoxin, then sacrificed.
- Brain tissue sections were analyzed for GDNF and NOS isomers using fluorescence deconvolution microscopy.
- Fluorescence was mapped and quantified for each probe.
Main Results:
- Immune cell influx observed in vulnerable brain areas.
- Three NOS isomers (iNOS, nNOS, eNOS) were synthesized, suggesting roles in neurodegeneration.
- NOS induction occurred earlier and persisted longer than GDNF induction.
Conclusions:
- GDNF's protective effects against neural destruction may be insufficient due to delayed and transient availability.
- NOS induction and glial activation are key inflammatory events in Parkinson's disease progression.
