Inhibitory effect of 4-O-methylhonokiol on lipopolysaccharide-induced neuroinflammation, amyloidogenesis and memory impairment via inhibition of nuclear factor-kappaB in vitroand in vivomodels

Lee Young-Jung, Choi Dong-Young, Choi, Kim, Lee Kiho, Cho, Jung, Han, Han Jin-Yi, Nam Sang-Yoon, Yun, Jeong, Oh Ki-Wan, Hong

Description

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 E 2 , 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 Aβ 1-42 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. Conclusion 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.

Sujets

• Alzheimer's disease
• Amyloid
• Lipopolysaccharide
• Magnolia officinalis
• Memory loss

Informations

• Publié par: biomed
• Publié le: 01 janvier 2012
• Nombre de lectures: 8
• Langue: English
• Poids de l'ouvrage: 2 Mo

Extrait

Leeet al.Journal of Neuroinflammation2012,9:35 http://www.jneuroinflammation.com/content/9/1/35

JOURNAL OF NEUROINFLAMMATION

R E S E A R C HOpen Access Inhibitory effect of 4Omethylhonokiol on lipopolysaccharideinduced neuroinflammation, amyloidogenesis and memory impairment via inhibition of nuclear factorkappaBin vitro andin vivomodels 1,2 1,21,2 33 4 YoungJung Lee, DongYoung Choi, Im Seop Choi, Ki Ho Kim , Young Hee Kim , Hwan Mook Kim , 4 51,2 1,21 66 Kiho Lee , Won Gil Cho , Jea Kyung Jung, Sang Bae Han, JinYi Han , SangYoon Nam , Young Won Yun , 7 1,21,2* Jae Hwang Jeong , KiWan Ohand Jin Tae Hong

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 ofMagnolia 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 (250μg/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 2μM). 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. Inin vitrostudy, 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 E 2 , tumor necrosis factora, and interleukin1bin the LPSstimulated cultured astrocytes. 4Omethylhonokiol also inhibited transcriptional and DNA binding activity of NFB via inhibition of IB 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 Ab 142 generation,b andg 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. Conclusion: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. Keywords:Alzheimer’s disease, Amyloid, Lipopolysaccharide, Neuroinflammation, 4Omethylhonokiol,Magnolia officinalis, Memory impairment

* Correspondence: [e-mail] 1 College of Pharmacy, Chungbuk National University, 12, Gaeshindong, Heungdukgu, Cheongju, Chungbuk 361763, Korea Full list of author information is available at the end of the article

© 2012 Lee et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.