title: Antineuroinflammatory effects of lycopene via activation of adenosine monophosphate-activated protein kinase-α1/heme oxygenase-1 pathways.
abstract: 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.
authors.affiliation: Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan.
authors.forename: Hsiao-Yun
authors.initials: HY
authors.lastname: Lin
authors.forename: Bor-Ren
authors.initials: BR
authors.lastname: Huang
authors.forename: Wei-Lan
authors.initials: WL
authors.lastname: Yeh
authors.forename: Chih-Hao
authors.initials: CH
authors.lastname: Lee
authors.forename: Shiang-Suo
authors.initials: SS
authors.lastname: Huang
authors.forename: Chih-Ho
authors.initials: CH
authors.lastname: Lai
authors.forename: Ho
authors.initials: H
authors.lastname: Lin
authors.forename: Dah-Yuu
authors.initials: DY
authors.lastname: Lu
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D002338:Carotenoids / Q000494:pharmacology* / Q000627:therapeutic use*; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors; D004195:Disease Models, Animal; D020820:Dyskinesias / Q000188:drug therapy* / Q000209:etiology*; D004789:Enzyme Activation / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000378:metabolism* / Q000502:physiology; D018836:Inflammation Mediators / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors; D000077276:Lycopene; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D017628:Microglia / Q000201:enzymology* / Q000378:metabolism* / Q000502:physiology; D009069:Movement Disorders; D011458:Prostaglandins E / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics
chemical_list: D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D052246:Cyclooxygenase 2 Inhibitors; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D011458:Prostaglandins E; D002338:Carotenoids; D051547:Heme Oxygenase-1; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; C548179:Prkaa1 protein, mouse; D055372:AMP-Activated Protein Kinases; D000077276:Lycopene
keywords: AMPKα1; COX-2; Lycopene; Microglia; heme oxygenase-1