title: Inhibitory effect of 4-O-methylhonokiol on lipopolysaccharide-induced neuroinflammation, amyloidogenesis and memory impairment via inhibition of nuclear factor-kappaB in vitro and in vivo models.
abstract: BACKGROUND
  Neuroinflammation is important in the pathogenesis and progression of Alzheimer disease (AD). Previously, we demonstrated that lipopolysaccharide (LPS)-induced neuroinflammation caused memory impairments. In the present study, we investigated the possible preventive effects of 4-O-methylhonokiol, a constituent of Magnolia officinalis, on memory deficiency caused by LPS, along with the underlying mechanisms.
  
  
  METHODS
  We investigated whether 4-O-methylhonokiol (0.5 and 1 mg/kg in 0.05% ethanol) prevents memory dysfunction and amyloidogenesis on AD model mice by intraperitoneal LPS (250 μg/kg daily 7 times) injection. In addition, LPS-treated cultured astrocytes and microglial BV-2 cells were investigated for anti-neuroinflammatory and anti-amyloidogenic effect of 4-O-methylhonkiol (0.5, 1 and 2 μM).
  
  
  RESULTS
  Oral administration of 4-O-methylhonokiol ameliorated LPS-induced memory impairment in a dose-dependent manner. In addition, 4-O-methylhonokiol prevented the LPS-induced expression of inflammatory proteins; inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) as well as activation of astrocytes (expression of glial fibrillary acidic protein; GFAP) in the brain. In in vitro study, we also found that 4-O-methylhonokiol suppressed the expression of iNOS and COX-2 as well as the production of reactive oxygen species, nitric oxide, prostaglandin E2, tumor necrosis factor-α, and interleukin-1β in the LPS-stimulated cultured astrocytes. 4-O-methylhonokiol also inhibited transcriptional and DNA binding activity of NF-κB via inhibition of IκB degradation as well as p50 and p65 translocation into nucleus of the brain and cultured astrocytes. Consistent with the inhibitory effect on neuroinflammation, 4-O-methylhonokiol inhibited LPS-induced Aβ1-42 generation, β- and γ-secretase activities, and expression of amyloid precursor protein (APP), BACE1 and C99 as well as activation of astrocytes and neuronal cell death in the brain, in cultured astrocytes and in microglial BV-2 cells.
  
  
  CONCLUSIONS
  These results suggest that 4-O-methylhonokiol inhibits LPS-induced amyloidogenesis via anti-inflammatory mechanisms. Thus, 4-O-methylhonokiol can be a useful agent against neuroinflammation-associated development or the progression of AD.
authors.affiliation: College of Pharmacy, Chungbuk National University, 12, Gaeshin-dong, Heungduk-gu, Cheongju, Chungbuk 361-763, Korea.
authors.forename: Young-Jung
authors.initials: YJ
authors.lastname: Lee
authors.forename: Dong-Young
authors.initials: DY
authors.lastname: Choi
authors.forename: Im Seop
authors.initials: IS
authors.lastname: Choi
authors.forename: Ki Ho
authors.initials: KH
authors.lastname: Kim
authors.forename: Young Hee
authors.initials: YH
authors.lastname: Kim
authors.forename: Hwan Mook
authors.initials: HM
authors.lastname: Kim
authors.forename: Kiho
authors.initials: K
authors.lastname: Lee
authors.forename: Won Gil
authors.initials: WG
authors.lastname: Cho
authors.forename: Jea Kyung
authors.initials: JK
authors.lastname: Jung
authors.forename: Sang Bae
authors.initials: SB
authors.lastname: Han
authors.forename: Jin-Yi
authors.initials: JY
authors.lastname: Han
authors.forename: Sang-Yoon
authors.initials: SY
authors.lastname: Nam
authors.forename: Young Won
authors.initials: YW
authors.lastname: Yun
authors.forename: Jae Hwang
authors.initials: JH
authors.lastname: Jeong
authors.forename: Ki-Wan
authors.initials: KW
authors.lastname: Oh
authors.forename: Jin Tae
authors.initials: JT
authors.lastname: Hong
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D001253:Astrocytes / Q000187:drug effects; D001362:Avoidance Learning / Q000187:drug effects; D001713:Biphenyl Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002461:Cell Line, Transformed; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D024202:Electrophoretic Mobility Shift Assay; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy*; D017705:Lignans / Q000494:pharmacology / Q000627:therapeutic use*; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008813:Mice, Inbred ICR; D017628:Microglia / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism
chemical_list: C542058:4-O-methylhonokiol; D016229:Amyloid beta-Peptides; D000893:Anti-Inflammatory Agents; D001713:Biphenyl Compounds; D016207:Cytokines; D005904:Glial Fibrillary Acidic Protein; D017705:Lignans; D008070:Lipopolysaccharides; D016328:NF-kappa B; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D009569:Nitric Oxide; D051546:Cyclooxygenase 2; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509281:Bace1 protein, rat; D015232:Dinoprostone