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Published on: January 7, 2014
Presymptomatic MPTP Mice Show Neurotrophic S100B/mRAGE Striatal Levels
Sofia D Viana1,2,3, Rosa C Fernandes1,2, Paula M Canas1,2
1Laboratory of Pharmacology and Experimental Therapeutics/IBILI, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
Aims:
Astrocytic S100B and receptor for advanced glycation endproducts (RAGE) have been implicated in Parkinson׳s disease (PD) pathogenesis through yet unclear mechanisms. This study attempted to characterize S100B/mRAGE (signaling isoform) axis in a dying-back dopaminergic (DAergic) axonopathy setting, which mimics an early event of PD pathology.
Methods:
C57BL/6 mice were submitted to a chronic MPTP paradigm (20 mg/kg i.p., 2 i.d-12 h apart, 5 days/week for 2 weeks) and euthanized 7 days posttreatment to assess mRAGE cellular distribution and S100B/mRAGE density in striatum, after probing their locomotor activity (pole test and rotarod). Dopaminergic status, oxidative stress, and gliosis were also measured (HPLC-ED, WB, IHC).
Results:
This MPTP regimen triggered increased oxidative stress (augmented HNE levels), gliosis (GS/Iba1-reactive morphology), loss of DAergic fibers (decreased tyrosine hydroxylase levels), and severe hypodopaminergia. Biochemical deficits were not translated into motor abnormalities, mimicking a presymptomatic PD period. Remarkably, striatal neurotrophic S100B/mRAGE levels and major neuronal mRAGE localization coexist with compensatory responses (3-fold increase in DA turnover), which are important to maintain normal motor function.
Conclusion:
Our findings rule out the involvement of S100B/mRAGE axis in striatal reactive gliosis, DAergic axonopathy and warrant further exploration of its neurotrophic effects in a presymptomatic compensatory PD stage, which is a fundamental period for successful implementation of therapeutic strategies.
Insights
The S100B/mRAGE axis does not appear to cause reactive gliosis or dopaminergic axonopathy in early Parkinson's disease. Its neurotrophic effects may be important in presymptomatic stages for therapeutic strategies.
Area of Science:
- Neuroscience
- Cell Biology
Background:
- Astrocytic S100B and the receptor for advanced glycation endproducts (RAGE) are implicated in Parkinson's disease (PD) pathogenesis.
- The precise mechanisms of their involvement, particularly in early PD pathology like dying-back dopaminergic (DAergic) axonopathy, remain unclear.
Purpose of the Study:
- To investigate the role of the S100B/mRAGE axis in a mouse model of early Parkinson's disease.
- To characterize the S100B/mRAGE signaling pathway in a dying-back DAergic axonopathy setting.
Main Methods:
- Mice were treated with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) to induce PD-like pathology.
- Locomotor activity, striatal S100B/mRAGE levels, DAergic status, oxidative stress, and gliosis were assessed.
Main Results:
- MPTP treatment induced oxidative stress, gliosis, loss of DAergic fibers, and hypodopaminergia, mimicking presymptomatic PD.
- Despite biochemical deficits, motor abnormalities were absent due to compensatory mechanisms, including increased DA turnover.
- Striatal S100B/mRAGE levels were elevated, with major neuronal localization, suggesting a potential neurotrophic role.
Conclusions:
- The S100B/mRAGE axis is not involved in striatal reactive gliosis or DAergic axonopathy in this PD model.
- Further research into the neurotrophic effects of S100B/mRAGE is warranted for presymptomatic PD therapeutic strategies.
