Microglia play an important role in the immune defense in the central nervous system. Activation of microglia leads to the production of excessive inflammatory molecules and deleterious consequences, including neuronal death.
Lycopene, 1 of the major
carotenoids present in tomatoes, has been shown to exert
antioxidant properties and to inhibit
cancer cell proliferation. However, the effects of
lycopene on neuroinflammatory responses in microglia remain unknown. In this study, we investigated the signaling pathways involved in
lycopene-inhibited expression of
cyclooxygenase (COX)-2 and
inflammation mediators in BV-2 microglia, mouse primary cultured microglia, and rat primary cultured microglia.
Lycopene inhibited the enhancement of
lipopolysaccharide (LPS)-induced
nuclear factor-kappaB (NF-κB) and
activator protein 1 (AP-1)
DNA binding activity. In the present study, we demonstrated that
lycopene inhibits LPS-induced COX-2 expression through
heme oxygenase-1 (HO-1) activation. Our results also demonstrate that stimulation with
lycopene increases the phosphorylation of liver
kinase B1 (LKB1),
calmodulin-dependent protein kinase II (
CaMKII), and
adenosine monophosphate-activated
protein kinase (AMPK)-α1. Treatment with AMPK inhibitors effectively antagonized
lycopene-stimulated HO-1 expression. Interestingly, we also found that
lycopene increased phospho-AMPKα1 accumulation in the nucleus in microglia. Preincubation of cells with HO-1 and AMPK selective pharmacological inhibitors dramatically reversed the inhibitory effect of
lycopene on LPS-induced COX-2 and
prostaglandin E2 production. Transfection of microglia with HO-1 and AMPKα
small interfering RNA (
siRNA) also effectively reversed the inhibitory effect of
lycopene on LPS-induced COX-2 expression. In a mouse model,
lycopene showed significant antineuroinflammatory effects on microglial activation and motor behavior deficits. These findings suggest that
lycopene-inhibited LPS-induced COX-2 expression is mediated by HO-1 activation through the AMPK pathway. Therefore,
lycopene might be useful as a therapeutic agent for the treatment of
neuroinflammation-associated disorders.