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Anti-RAGE antibody selectively blocks acute systemic inflammatory responses to LPS in serum, liver, CSF and striatum
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DOI：10.1016/j.bbi.2017.01.008.png)
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Abstract
En 中文
Systemic inflammation induces transient or permanent dysfunction in the brain by exposing it to soluble inflammatory mediators. The receptor for advanced glycation endproducts (RAGE) binds to distinct ligands mediating and increasing inflammatory processes. In this study we used an LPS-induced systemic inflammation model in rats to investigate the effect of blocking RAGE in serum, liver, cerebrospinal fluid (CSF) and brain (striatum, prefrontal cortex, ventral tegmental area and substantia nigra). Intraperitoneal injection of RAGE antibody (50 mu g/kg) was followed after 1 h by a single LPS (5 mg/kg) intraperitoneal injection. Twenty-four hours later, tissues were isolated for analysis. RAGE antibody reduced LPSinduced inflammatory effects in both serum and liver; the levels of proinflammatory cytokines (TNF-alpha, IL-1 beta) were decreased and the phosphorylation/activation of RAGE downstream targets (ERK1 /2, I kappa B and p65) in liver were significantly attenuated. RAGE antibody prevented LPS-induced effects on TNF alpha and IL-1 beta in CSF. In striatum, RAGE antibody inhibited increases in IL-1 beta, lba-1, GFAP, phosphoERK1/2 and phospho-tau (ser202), as well as the decrease in synaptophysin levels. These effects were caused by systemic RAGE inhibition, as RAGE antibody did not cross the blood-brain barrier. RAGE antibody also prevented striatal lipoperoxidation and activation of mitochondrial complex II. In conclusion, blockade of RAGE is able to inhibit inflammatory responses induced by LPS in serum, liver, CSF and brain. (C) 2017 Elsevier Inc. All rights reserved.
Keywords:
RAGE
Neuroinflammation
Systemic inflammation
LPS
Striatum
Neurodegeneration
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