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

Abstract 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...

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Autores principales:	Juciano Gasparotto, Camila Tiefensee Ribeiro, Rafael Calixto Bortolin, Nauana Somensi, Thallita Kelly Rabelo, Alice Kunzler, Natália Cabral Souza, Matheus Augusto de Bittencourt Pasquali, José Claudio Fonseca Moreira, Daniel Pens Gelain
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/ffb3602eb03b464ba25e09c194a671bc
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spelling	oai:doaj.org-article:ffb3602eb03b464ba25e09c194a671bc2021-12-02T16:06:07ZTargeted inhibition of RAGE in substantia nigra of rats blocks 6-OHDA–induced dopaminergic denervation10.1038/s41598-017-09257-32045-2322https://doaj.org/article/ffb3602eb03b464ba25e09c194a671bc2017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-09257-3https://doaj.org/toc/2045-2322Abstract 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 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 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.Juciano GasparottoCamila Tiefensee RibeiroRafael Calixto BortolinNauana SomensiThallita Kelly RabeloAlice KunzlerNatália Cabral SouzaMatheus Augusto de Bittencourt PasqualiJosé Claudio Fonseca MoreiraDaniel Pens GelainNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-12 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Juciano Gasparotto Camila Tiefensee Ribeiro Rafael Calixto Bortolin Nauana Somensi Thallita Kelly Rabelo Alice Kunzler Natália Cabral Souza Matheus Augusto de Bittencourt Pasquali José Claudio Fonseca Moreira Daniel Pens Gelain Targeted inhibition of RAGE in substantia nigra of rats blocks 6-OHDA–induced dopaminergic denervation
description	Abstract 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 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 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.
format	article
author	Juciano Gasparotto Camila Tiefensee Ribeiro Rafael Calixto Bortolin Nauana Somensi Thallita Kelly Rabelo Alice Kunzler Natália Cabral Souza Matheus Augusto de Bittencourt Pasquali José Claudio Fonseca Moreira Daniel Pens Gelain
author_facet	Juciano Gasparotto Camila Tiefensee Ribeiro Rafael Calixto Bortolin Nauana Somensi Thallita Kelly Rabelo Alice Kunzler Natália Cabral Souza Matheus Augusto de Bittencourt Pasquali José Claudio Fonseca Moreira Daniel Pens Gelain
author_sort	Juciano Gasparotto
title	Targeted inhibition of RAGE in substantia nigra of rats blocks 6-OHDA–induced dopaminergic denervation
title_short	Targeted inhibition of RAGE in substantia nigra of rats blocks 6-OHDA–induced dopaminergic denervation
title_full	Targeted inhibition of RAGE in substantia nigra of rats blocks 6-OHDA–induced dopaminergic denervation
title_fullStr	Targeted inhibition of RAGE in substantia nigra of rats blocks 6-OHDA–induced dopaminergic denervation
title_full_unstemmed	Targeted inhibition of RAGE in substantia nigra of rats blocks 6-OHDA–induced dopaminergic denervation
title_sort	targeted inhibition of rage in substantia nigra of rats blocks 6-ohda–induced dopaminergic denervation
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/ffb3602eb03b464ba25e09c194a671bc
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Targeted inhibition of RAGE in substantia nigra of rats blocks 6-OHDA–induced dopaminergic denervation

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