Targeted inhibition of RAGE in substantia nigra of rats blocks 6-OHDA-induced dopaminergic denervation

• Autor(a) principal: Gasparotto, Juciano
• Data de Publicação: 2017
• Outros Autores: Ribeiro, Camila Tiefensee, Bortolin, Rafael Calixto, Somensi, Nauana, Rabelo, Thallita Kelly, Kunzler, Alice, Souza, Natália Cabral, Pasquali, Matheus Augusto de Bittencourt, Moreira, Jose Claudio Fonseca, Gelain, Daniel Pens
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Institucional da UFRGS
• Texto Completo: http://hdl.handle.net/10183/225530
• topic: Produtos finais de glicosilação avançada; Sistema nervoso central; NF-kappa B; Doenças neurodegenerativas; Cell death in the nervous system; Membrane proteins

The receptor for advanced glycation endproducts (RAGE) is a pattern-recognition receptor associated with infammation in most cell types. RAGE up-regulates the expression of proinfammatory 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 μg per rat), injected concomitantly with 6-OHDA (10 μg per rat) into the SN, inhibited the increase in RAGE, activation of ERK1/2, Src and nuclear translocation of NF-kB p65 subunit in the SN. RAGE inhibition blocked glial fbrillary 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 signifcantly inhibited by RAGE blocking. Finally, FPS-ZM1 attenuated locomotory and exploratory defcits induced by 6-OHDA. Our results demonstrate that RAGE is an essential component in the neuroinfammation and dopaminergic denervation induced by 6-OHDA in the SN. Selective inhibition of RAGE may ofer perspectives for therapeutic approaches.