期刊
CNS NEUROSCIENCE & THERAPEUTICS
卷 22, 期 5, 页码 396-403出版社
WILEY
DOI: 10.1111/cns.12508
关键词
MPTP; Presymptomatic; RAGE; S100B; Striatum
资金
- FCT, Portugal [PEst-C/SAU/UI3282/2013, UID/NEU/04539/2013]
- COMPETE-FEDER
- Fundo Comunitario Europeu (FEDER)
- Fundacao para a Ciencia e a Tecnologia (FCT, Portugal) [SFRH/BD/78166/2011]
- [EXPL/DTP-DES/0104/2013]
- Fundação para a Ciência e a Tecnologia [SFRH/BD/78166/2011, EXPL/DTP-DES/0104/2013] Funding Source: FCT
AimsAstrocytic 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. MethodsC57BL/6 mice were submitted to a chronic MPTP paradigm (20mg/kg i.p., 2 i.d-12h apart, 5days/week for 2weeks) and euthanized 7days 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). ResultsThis 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. ConclusionOur 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.
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