期刊
SCIENTIFIC REPORTS
卷 7, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41598-017-09257-3
关键词
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资金
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) [400437/2013-9, 443514/2014-3, 401260/2014-3]
- FAPERGS [2299-2551/14-6]
- Propesq-UFRGS
- Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES)
The receptor for advanced glycation endproducts (RAGE) is a pattern-recognition receptor associated with inflammation in most cell types. RAGE up-regulates the expression of proinflammatory mediators and its own expression via activation of NF-kB. Recent works have proposed a role for RAGE in Parkinson's disease (PD). In this study, we used the multimodal blocker of RAGE FPS-ZM1, which has become available recently, to selectively inhibit RAGE in the substantia nigra (SN) of rats intracranially injected with 6-hydroxydopamine (6-OHDA). FPS-ZM1 (40 mu g per rat), injected concomitantly with 6-OHDA (10 mu g per rat) into the SN, inhibited the increase in RAGE, activation of ERK1/2, Src and nuclear translocation of NF-kappa B p65 subunit in the SN. RAGE inhibition blocked glial fibrillary acidic protein and Iba-1 upregulation as well as associated astrocyte and microglia activation. Circulating cytokines in serum and CSF were also decreased by FPS-ZM1 injection. The loss of tyrosine hydroxylase and NeuN-positive neurons was significantly inhibited by RAGE blocking. Finally, FPS-ZM1 attenuated locomotory and exploratory deficits induced by 6-OHDA. Our results demonstrate that RAGE is an essential component in the neuroinflammation and dopaminergic denervation induced by 6-OHDA in the SN. Selective inhibition of RAGE may offer perspectives for therapeutic approaches.
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