title: Regulation of striatal astrocytic receptor for advanced glycation end-products variants in an early stage of experimental Parkinson's disease.
abstract: Convincing evidence indicates that advanced glycation end-products and danger-associated protein S100B play a role in Parkinson's disease (PD). These agents operate through the receptor for advanced glycation end-products (RAGE), which displays distinct isoforms playing protective/deleterious effects. However, the nature of RAGE variants has been overlooked in PD studies. Hence, we attempted to characterize RAGE regulation in early stages of PD striatal pathology. A neurotoxin-based rodent model of PD was used in this study, through administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to C57BL/6 mice. Animals were killed 6 h post-MPTP to assess S100B/RAGE contents (RT-qPCR, ELISA) and RAGE isoform density (WB) and cellular distribution (immunohistochemistry). Dopaminergic and gliotic status were also mapped (HPLC-ED, WB, immunohistochemistry). At this preliminary stage of MPTP-induced PD in mice, RAGE inhibitory isoforms were increased whereas full-length RAGE was not affected. This putative cytoprotective RAGE phenotype paired an inflammatory and pro-oxidant setting fueling DAergic denervation. Increased RAGE inhibitory variants occur in astrocytes showing higher S100B density but no overt signs of hypertrophy or NF-κB activation, a canonical effector of RAGE. These findings expand our understanding of the toxic effect of MPTP on striatum and offer first in vivo evidence of RAGE being a responder in early stages of astrogliosis dynamics, supporting a protective rather tissue-destructive phenotype of RAGE in the initial phase of PD degeneration. These data lay the groundwork for future studies on the relevance of astrocytic RAGE in DAergic neuroprotection strategies. We report increased antagonistic RAGE variants paralleling S100B up-regulation in early stages of MPTP-induced astrogliosis dynamics . We propose that selective RAGE regulation reflects a self-protective mechanism to maintain low levels of RAGE ligands , preventing long-term inflammation and oxidative stress arising from sustained ligands/flRAGE activation . Understanding loss of RAGE protective response to stress may provide new therapeutic options to halt or slow down dopaminergic axonopathy and, ultimately, neuronal death .
authors.affiliation: Laboratory of Pharmacology and Experimental Therapeutics/IBILI, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.|CNC.IBILI - University of Coimbra, Coimbra, Portugal.|Polytechnic Institute of Coimbra, ESTESC-Coimbra Health School, Pharmacy, Coimbra, Portugal.
authors.forename: Sofia D
authors.initials: SD
authors.lastname: Viana
authors.affiliation: CNC.IBILI - University of Coimbra, Coimbra, Portugal.|Achucarro Basque Center for Neuroscience, Zamudio, Bizkaia, Spain.|Ikerbasque Foundation, Bilbao, Bizkaia, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Valero
authors.affiliation: Institute of Immunology - Faculty of Medicine, University of Coimbra, Coimbra, Portugal.|Immunology and Oncology Laboratory, Center for Neurosciences and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal.|Center of Investigation in Environment, Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors.forename: Paulo
authors.initials: P
authors.lastname: Rodrigues-Santos
authors.affiliation: Immunology and Oncology Laboratory, Center for Neurosciences and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal.
authors.forename: Patrícia
authors.initials: P
authors.lastname: Couceiro
authors.affiliation: Laboratory of Pharmacology and Experimental Therapeutics/IBILI, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.|CNC.IBILI - University of Coimbra, Coimbra, Portugal.
authors.forename: Andréa M
authors.initials: AM
authors.lastname: Silva
authors.affiliation: UCIBIO-REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal.
authors.forename: Félix
authors.initials: F
authors.lastname: Carvalho
authors.affiliation: Neurochemistry Laboratory, Division of Neurotoxicology, National Center of Toxicological Research/Food and Drug Administration, Jefferson, Arkansas, USA.
authors.forename: Syed F
authors.initials: SF
authors.lastname: Ali
authors.affiliation: Laboratory of Pharmacology and Experimental Therapeutics/IBILI, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.|CNC.IBILI - University of Coimbra, Coimbra, Portugal.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Fontes-Ribeiro
authors.affiliation: Laboratory of Pharmacology and Experimental Therapeutics/IBILI, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.|CNC.IBILI - University of Coimbra, Coimbra, Portugal.
authors.forename: Frederico C
authors.initials: FC
authors.lastname: Pereira
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D003342:Corpus Striatum / Q000378:metabolism*; D004195:Disease Models, Animal; D008297:Male; D008810:Mice, Inbred C57BL; D017072:Neostriatum / Q000378:metabolism*; D010300:Parkinson Disease / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products / Q000235:genetics / Q000378:metabolism*
chemical_list: C000593873:Ager protein, mouse; D017382:Reactive Oxygen Species; D000067759:Receptor for Advanced Glycation End Products
keywords: MPTP; RAGE isoforms; S100B; astrocytes; striatum