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-1β (IL-1β) 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-1β 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-1β 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-1β 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.
- Alzheimer's disease
- Extracellular signal-regulated kinase 1/2
- Monocyte chemoattractant protein-1