title: Resveratrol reduces glutamate-mediated monocyte chemotactic protein-1 expression via inhibition of extracellular signal-regulated kinase 1/2 pathway in rat hippocampal slice cultures.
abstract: Published evidence has linked glutamate with the pathogenesis of Alzheimer's disease (AD) and the up-regulation of a variety of chemokines, including monocyte chemotactic protein-1 (MCP-1)/chemokine ligand 2, with AD-associated pathological changes. In this study, we assessed the potential molecular basis for the role of glutamate in hippocampal inflammation by determining its effects on MCP-1 induction. We also attempted to identify the mechanism by which resveratrol (trans-3,5,4'-trihydroxystilbene), a polyphenolic phytostilbene, modulates the expression of MCP-1 in the glutamate-stimulated hippocampus. An ex vivo study using rat hippocampal slices demonstrated a time- and dose-dependent increase in MCP-1 release from glutamate-exposed hippocampus. This increase was accompanied by enhanced MCP-1 gene expression via the activation of the MEK/extracellular signal-regulated kinase (ERK) pathway and interleukin-1beta (IL-1beta) expression. The inhibition of the MEK/ERK pathway with SL327, which is capable of crossing the blood-brain barrier, nearly abolished the observed glutamate-induced effects. Furthermore, anti-IL-1beta antibodies suppressed the glutamate-induced expression of MCP-1 mRNA and protein, whereas an isotype-matched antibody exerted only minimal effects. It is worthy of note that resveratrol, to a similar degree as SL327, down-regulated glutamate-induced IL-1beta expression and reduced the expression of MCP-1 mRNA and protein release via the inactivation of ERK1/2. These results indicate that the activation of the MEK/ERK pathway and the consequent IL-1beta expression are essential for glutamate-stimulated MCP-1 production in the hippocampus. Additionally, our data reveal an anti-inflammatory mechanism of resveratrol involving the inactivation of the ERK1/2 pathway in the hippocampus, which is linked principally to AD-associated cognitive dysfunction.
authors.affiliation: Department of Microbiology, School of Medicine, Ewha Medical Research Institute, Ewha Womans University, Seoul, Korea.
authors.forename: Eun Ok
authors.initials: EO
authors.lastname: Lee
authors.forename: Hee Ju
authors.initials: HJ
authors.lastname: Park
authors.forename: Jihee Lee
authors.initials: JL
authors.lastname: Kang
authors.forename: Hye-Sun
authors.initials: HS
authors.lastname: Kim
authors.forename: Young Hae
authors.initials: YH
authors.lastname: Chong
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000906:Antibodies / Q000494:pharmacology; D018932:Chemokine CCL2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects*; D018698:Glutamic Acid / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism*; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009924:Organ Culture Techniques; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects*; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: D000906:Antibodies; D018932:Chemokine CCL2; D004791:Enzyme Inhibitors; D053583:Interleukin-1beta; D012333:RNA, Messenger; D013267:Stilbenes; D018698:Glutamic Acid; D007770:L-Lactate Dehydrogenase; D048052:Mitogen-Activated Protein Kinase 3; D000077185:Resveratrol