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Open Access 01-12-2017 | Original Paper

(E)-2-Methoxy-4-(3-(4-methoxyphenyl) prop-1-en-1-yl) Phenol Ameliorates LPS-Mediated Memory Impairment by Inhibition of STAT3 Pathway

Authors: Ji Yeon Choi, Chul Ju Hwang, Do Yeon Lee, Sun Mi Gu, Hee Pom Lee, Dong Young Choi, Ki Wan Oh, Sang-Bae Han, Jin Tae Hong

Published in: NeuroMolecular Medicine | Issue 4/2017

Abstract

Alzheimer’s disease (AD) is pathologically characterized by an excessive accumulation of amyloid-beta (Aβ) fibrils within the brain. We tested the anti-inflammatory and anti-amyloidogenic effects of (E)-2-methoxy-4-(3-(4-methoxyphenyl) prop-1-en-1-yl) phenol (MMPP), a selective signal transducer and activator of transcription 3 (STAT3) inhibitor. We examined whether MMPP (5 mg/kg in drinking water for 1 month) prevents amyloidogenesis and cognitive impairment on AD model mice induced by intraperitoneal LPS (250 μg/kg daily 7 times) injections. Additionally, we investigated the anti-neuroinflammatory and anti-amyloidogenic effect of MMPP (1, 5, and 10 μg/mL) in LPS (1 μg/mL)-treated cultured astrocytes and microglial BV-2 cells. MMPP treatment reduced LPS-induced memory loss. This memory recovery effect was associated with the reduction of LPS-induced inflammatory proteins; cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) as well as activation of microglial cells and astrocytes in the brain. Furthermore, MMPP reduced LPS-induced β-secretase and Aβ generation. In in vitro study, LPS-induced expression of inflammatory proteins and amyloidogenic proteins was decreased in microglial BV-2 cells and cultured astrocytes by MMPP treatment. Moreover, MMPP treatment suppressed DNA binding activities of the activation of STAT3 in in vivo and in vitro. These results indicated that MMPP inhibits LPS-induced amyloidogenesis and neuroinflammation via inhibition of STAT3.

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Ban, J. O., Kim, D. H., Lee, H. P., Hwang, C. J., Shim, J. H., Kim, D. J., et al. (2014). Anti-arthritis effects of (E)-2,4-bis(p-hydroxyphenyl)-2-butenal are mediated by inhibition of the STAT3 pathway. British Journal of Pharmacology, 171(11), 2900–2912. doi:10.1111/bph.12619.CrossRefPubMedPubMedCentral

Biesmans, S., Meert, T. F., Bouwknecht, J. A., Acton, P. D., Davoodi, N., De Haes, P., et al. (2013). Systemic immune activation leads to neuroinflammation and sickness behavior in mice. Mediators of Inflammation, 2013, 271359. doi:10.1155/2013/271359.CrossRefPubMedPubMedCentral

Carret-Rebillat, A. S., Pace, C., Gourmaud, S., Ravasi, L., Montagne-Stora, S., Longueville, S., et al. (2015). Neuroinflammation and Abeta accumulation linked to systemic inflammation are decreased by genetic PKR down-regulation. Scientific Reports, 5, 8489. doi:10.1038/srep08489.CrossRefPubMedPubMedCentral

Chen, J., Buchanan, J. B., Sparkman, N. L., Godbout, J. P., Freund, G. G., & Johnson, R. W. (2008). Neuroinflammation and disruption in working memory in aged mice after acute stimulation of the peripheral innate immune system. Brain, Behavior, and Immunity, 22(3), 301–311. doi:10.1016/j.bbi.2007.08.014.CrossRefPubMed

Cherubini, E., & Miles, R. (2015). The CA3 region of the hippocampus: how is it? What is it for? How does it do it? Frontiers in Cellular Neuroscience, 9, 19. doi:10.3389/fncel.2015.00019.CrossRefPubMedPubMedCentral

Chiba, T., Yamada, M., & Aiso, S. (2009). Targeting the JAK2/STAT3 axis in Alzheimer’s disease. Expert Opinion on Therapeutic Targets, 13(10), 1155–1167. doi:10.1517/14728220903213426.CrossRefPubMed

Cho, S. H., Park, M. H., Lee, H. P., Back, M. K., Sung, H. C., Chang, H. W., et al. (2014). (E)-2,4-Bis(p-hydroxyphenyl)-2-butenal enhanced TRAIL-induced apoptosis in ovarian cancer cells through downregulation of NF-kappaB/STAT3 pathway. Archives of Pharmacal Research, 37(5), 652–661. doi:10.1007/s12272-013-0326-9.CrossRefPubMed

Choi, D. Y., Lee, J. W., Lin, G., Lee, Y. K., Lee, Y. H., Choi, I. S., et al. (2012). Obovatol attenuates LPS-induced memory impairments in mice via inhibition of NF-kappaB signaling pathway. Neurochemistry International, 60(1), 68–77. doi:10.1016/j.neuint.2011.11.005.CrossRefPubMed

Cotter, D. R., Pariante, C. M., & Everall, I. P. (2001). Glial cell abnormalities in major psychiatric disorders: The evidence and implications. Brain Research Bulletin, 55(5), 585–595.CrossRefPubMed

DiCarlo, G., Wilcock, D., Henderson, D., Gordon, M., & Morgan, D. (2001). Intrahippocampal LPS injections reduce Abeta load in APP + PS1 transgenic mice. Neurobiology of Aging, 22(6), 1007–1012.CrossRefPubMed

Eikelenboom, P., Bate, C., Van Gool, W. A., Hoozemans, J. J., Rozemuller, J. M., Veerhuis, R., et al. (2002). Neuroinflammation in Alzheimer’s disease and prion disease. Glia, 40(2), 232–239. doi:10.1002/glia.10146.CrossRefPubMed

Fan, L., Wang, T., Chang, L., Song, Y., Wu, Y., & Ma, D. (2014). Systemic inflammation induces a profound long term brain cell injury in rats. Acta Neurobiologiae Expermentalis (Wars), 74(3), 298–306.

Farrimond, L. E., Roberts, E., & McShane, R. (2012). Memantine and cholinesterase inhibitor combination therapy for Alzheimer’s disease: A systematic review. British Medical Journal Open, 2(3), e000917. doi:10.1136/bmjopen-2012-000917.

Gu, S. M., Park, M. H., Hwang, C. J., Song, H. S., Lee, U. S., Han, S. B., et al. (2015). Bee venom ameliorates lipopolysaccharide-induced memory loss by preventing NF-kappaB pathway. Journal of Neuroinflammation, 12, 124. doi:10.1186/s12974-015-0344-2.CrossRefPubMedPubMedCentral

Hashimoto, Y., Suzuki, H., Aiso, S., Niikura, T., Nishimoto, I., & Matsuoka, M. (2005). Involvement of tyrosine kinases and STAT3 in Humanin-mediated neuroprotection. Life Sciences, 77(24), 3092–3104. doi:10.1016/j.lfs.2005.03.031.CrossRefPubMed

Hauss-Wegrzyniak, B., Lukovic, L., Bigaud, M., & Stoeckel, M. E. (1998). Brain inflammatory response induced by intracerebroventricular infusion of lipopolysaccharide: An immunohistochemical study. Brain Research, 794(2), 211–224.CrossRefPubMed

Henry, C. J., Huang, Y., Wynne, A. M., & Godbout, J. P. (2009). Peripheral lipopolysaccharide (LPS) challenge promotes microglial hyperactivity in aged mice that is associated with exaggerated induction of both pro-inflammatory IL-1beta and anti-inflammatory IL-10 cytokines. Brain, Behavior, and Immunity, 23(3), 309–317. doi:10.1016/j.bbi.2008.09.002.CrossRefPubMed

Holsinger, R. M., McLean, C. A., Beyreuther, K., Masters, C. L., & Evin, G. (2002). Increased expression of the amyloid precursor beta-secretase in Alzheimer’s disease. Annals of Neurology, 51(6), 783–786. doi:10.1002/ana.10208.CrossRefPubMed

Hwang, C. J., Park, M. H., Hwang, J. Y., Kim, J. H., Yun, N. Y., Oh, S. Y., et al. (2016). CCR5 deficiency accelerates lipopolysaccharide-induced astrogliosis, amyloid-beta deposit and impaired memory function. Oncotarget. doi:10.18632/oncotarget.7453.

Jin, P., Kim, J. A., Choi, D. Y., Lee, Y. J., Jung, H. S., & Hong, J. T. (2013). Anti-inflammatory and anti-amyloidogenic effects of a small molecule, 2,4-bis(p-hydroxyphenyl)-2-butenal in Tg2576 Alzheimer’s disease mice model. Journal of Neuroinflammation, 10, 2. doi:10.1186/1742-2094-10-2.PubMedPubMedCentral

Kesner, R. P. (2007). Behavioral functions of the CA3 subregion of the hippocampus. Learning & Memory, 14(11), 771–781. doi:10.1101/lm.688207.CrossRef

Kim, J. A., Yun, H. M., Jin, P., Lee, H. P., Han, J. Y., Udumula, V., et al. (2014). Inhibitory effect of a 2,4-bis(4-hydroxyphenyl)-2-butenal diacetate on neuro-inflammatory reactions via inhibition of STAT1 and STAT3 activation in cultured astrocytes and microglial BV-2 cells. Neuropharmacology, 79, 476–487. doi:10.1016/j.neuropharm.2013.06.032.CrossRefPubMed

Korolainen, M. A., Auriola, S., Nyman, T. A., Alafuzoff, I., & Pirttila, T. (2005). Proteomic analysis of glial fibrillary acidic protein in Alzheimer’s disease and aging brain. Neurobiology of Diseases, 20(3), 858–870. doi:10.1016/j.nbd.2005.05.021.CrossRef

Lee, Y. J., Choi, D. Y., Choi, I. S., Kim, K. H., Kim, Y. H., Kim, H. M., et al. (2012a). 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. Journal of Neuroinflammation, 9, 35. doi:10.1186/1742-2094-9-35.PubMedPubMedCentral

Lee, Y. J., Choi, D. Y., Lee, Y. K., Lee, Y. M., Han, S. B., Kim, Y. H., et al. (2012b). 4-O-methylhonokiol prevents memory impairment in the Tg2576 transgenic mice model of Alzheimer’s disease via regulation of beta-secretase activity. Journal of Alzheimer’s Disease, 29(3), 677–690. doi:10.3233/JAD-2012-111835.PubMed

Lee, Y. J., Choi, I. S., Park, M. H., Lee, Y. M., Song, J. K., Kim, Y. H., et al. (2011). 4-O-Methylhonokiol attenuates memory impairment in presenilin 2 mutant mice through reduction of oxidative damage and inactivation of astrocytes and the ERK pathway. Free Radical Biology and Medicine, 50(1), 66–77. doi:10.1016/j.freeradbiomed.2010.10.698.CrossRefPubMed

Lee, Y. J., Choi, D. Y., Yun, Y. P., Han, S. B., Kim, H. M., Lee, K., et al. (2013a). Ethanol extract of Magnolia officinalis prevents lipopolysaccharide-induced memory deficiency via its antineuroinflammatory and antiamyloidogenic effects. Phytotherapy Research, 27(3), 438–447. doi:10.1002/ptr.4740.CrossRefPubMed

Lee, Y. J., Choi, D. Y., Yun, Y. P., Han, S. B., Oh, K. W., & Hong, J. T. (2013b). Epigallocatechin-3-gallate prevents systemic inflammation-induced memory deficiency and amyloidogenesis via its anti-neuroinflammatory properties. Journal of Nutritional Biochemistry, 24(1), 298–310. doi:10.1016/j.jnutbio.2012.06.011.CrossRefPubMed

Lee, J. W., Lee, Y. K., Yuk, D. Y., Choi, D. Y., Ban, S. B., Oh, K. W., et al. (2008). Neuro-inflammation induced by lipopolysaccharide causes cognitive impairment through enhancement of beta-amyloid generation. Journal of Neuroinflammation, 5, 37. doi:10.1186/1742-2094-5-37.CrossRefPubMedPubMedCentral

Lim, G. P., Yang, F., Chu, T., Chen, P., Beech, W., Teter, B., et al. (2000). Ibuprofen suppresses plaque pathology and inflammation in a mouse model for Alzheimer’s disease. Journal of Neuroscience, 20(15), 5709–5714.PubMed

Lisman, J. E. (1999). Relating hippocampal circuitry to function: Recall of memory sequences by reciprocal dentate-CA3 interactions. Neuron, 22(2), 233–242.CrossRefPubMed

Liu, L., Martin, R., Kohler, G., & Chan, C. (2013). Palmitate induces transcriptional regulation of BACE1 and presenilin by STAT3 in neurons mediated by astrocytes. Experimental Neurology, 248, 482–490. doi:10.1016/j.expneurol.2013.08.004.CrossRefPubMedPubMedCentral

Madeddu, S., Woods, T. A., Mukherjee, P., Sturdevant, D., Butchi, N. B., & Peterson, K. E. (2015). Identification of Glial activation markers by comparison of transcriptome changes between astrocytes and microglia following innate immune stimulation. PLoS ONE, 10(7), e0127336. doi:10.1371/journal.pone.0127336.CrossRefPubMedPubMedCentral

Madronal, N., Delgado-Garcia, J. M., Fernandez-Guizan, A., Chatterjee, J., Kohn, M., Mattucci, C., et al. (2016). Rapid erasure of hippocampal memory following inhibition of dentate gyrus granule cells. Nature Communications, 7, 10923. doi:10.1038/ncomms10923.CrossRefPubMedPubMedCentral

Masocha, W. (2009). Systemic lipopolysaccharide (LPS)-induced microglial activation results in different temporal reduction of CD200 and CD200 receptor gene expression in the brain. Journal of Neuroimmunology, 214(1–2), 78–82. doi:10.1016/j.jneuroim.2009.06.022.CrossRefPubMed

Morris, R. (1984). Developments of a water-maze procedure for studying spatial learning in the rat. Journal of Neuroscience Methods, 11(1), 47–60.CrossRefPubMed

Niemand, C., Nimmesgern, A., Haan, S., Fischer, P., Schaper, F., Rossaint, R., et al. (2003). Activation of STAT3 by IL-6 and IL-10 in primary human macrophages is differentially modulated by suppressor of cytokine signaling 3. The Journal of Immunology, 170(6), 3263–3272.CrossRefPubMed

Noh, H., Jeon, J., & Seo, H. (2014). Systemic injection of LPS induces region-specific neuroinflammation and mitochondrial dysfunction in normal mouse brain. Neurochemistry International, 69, 35–40. doi:10.1016/j.neuint.2014.02.008.CrossRefPubMed

Park, S. J., Shin, E. J., Min, S. S., An, J., Li, Z., Hee Chung, Y., et al. (2013). Inactivation of JAK2/STAT3 signaling axis and downregulation of M1 mAChR cause cognitive impairment in klotho mutant mice, a genetic model of aging. Neuropsychopharmacology, 38(8), 1426–1437. doi:10.1038/npp.2013.39.CrossRefPubMedPubMedCentral

Park, C. W., Song, Y. S., Lee, H. P., Hong, J. T., & Yoon, D. Y. (2017). (E)-2-methoxy-4-(3-(4-methoxyphenyl)prop-1-en-1-yl)phenol induces apoptosis in HeLa cervical cancer cells via the extrinsic apoptotic pathway. Journal of Microbiology and Biotechnology. doi:10.4014/jmb.1703.03060.

Parsons, C. G., Danysz, W., Dekundy, A., & Pulte, I. (2013). Memantine and cholinesterase inhibitors: Complementary mechanisms in the treatment of Alzheimer’s disease. Neurotoxicity Research, 24(3), 358–369. doi:10.1007/s12640-013-9398-z.CrossRefPubMedPubMedCentral

Pettenati, C., Annicchiarico, R., & Caltagirone, C. (2003). Clinical pharmacology of anti-Alzheimer drugs. Fundamental & Clinical Pharmacology, 17(6), 659–672.CrossRef

Pop, V., Head, E., Berchtold, N. C., Glabe, C. G., Studzinski, C. M., Weidner, A. M., et al. (2012). Abeta aggregation profiles and shifts in APP processing favor amyloidogenesis in canines. Neurobiology of Aging, 33(1), 108–120. doi:10.1016/j.neurobiolaging.2010.02.008.CrossRefPubMed

Pulawski, W., Ghoshdastider, U., Andrisano, V., & Filipek, S. (2012). Ubiquitous amyloids. Applied Biochemistry and Biotechnology, 166(7), 1626–1643. doi:10.1007/s12010-012-9549-3.CrossRefPubMedPubMedCentral

Qin, L., Wu, X., Block, M. L., Liu, Y., Breese, G. R., Hong, J. S., et al. (2007). Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia, 55(5), 453–462. doi:10.1002/glia.20467.CrossRefPubMedPubMedCentral

Sambamurti, K., Kinsey, R., Maloney, B., Ge, Y. W., & Lahiri, D. K. (2004). Gene structure and organization of the human beta-secretase (BACE) promoter. The FASEB Journal, 18(9), 1034–1036. doi:10.1096/fj.03-1378fje.PubMed

Schnabel, J. (2010). Protein folding: The dark side of proteins. Nature, 464(7290), 828–829. doi:10.1038/464828a.CrossRefPubMed

Sheng, J. G., Bora, S. H., Xu, G., Borchelt, D. R., Price, D. L., & Koliatsos, V. E. (2003). Lipopolysaccharide-induced-neuroinflammation increases intracellular accumulation of amyloid precursor protein and amyloid beta peptide in APPswe transgenic mice. Neurobiology of Diseases, 14(1), 133–145.CrossRef

Sola, C., Casal, C., Tusell, J. M., & Serratosa, J. (2002). Astrocytes enhance lipopolysaccharide-induced nitric oxide production by microglial cells. European Journal of Neuroscience, 16(7), 1275–1283.CrossRefPubMed

Son, D. J., Kim, D. H., Nah, S. S., Park, M. H., Lee, H. P., Han, S. B., et al. (2016). Novel synthetic (E)-2-methoxy-4-(3-(4-methoxyphenyl) prop-1-en-1-yl) phenol inhibits arthritis by targeting signal transducer and activator of transcription 3. Scientific Reports, 6, 36852. doi:10.1038/srep36852.CrossRefPubMedPubMedCentral

Song, S. Y., Jung, Y. Y., Hwang, C. J., Lee, H. P., Sok, C. H., Kim, J. H., et al. (2014). Inhibitory effect of ent-Sauchinone on amyloidogenesis via inhibition of STAT3-mediated NF-kappaB activation in cultured astrocytes and microglial BV-2 cells. Journal of Neuroinflammation, 11, 118. doi:10.1186/1742-2094-11-118.CrossRefPubMedPubMedCentral

Wan, J., Fu, A. K., Ip, F. C., Ng, H. K., Hugon, J., Page, G., et al. (2010). Tyk2/STAT3 signaling mediates beta-amyloid-induced neuronal cell death: implications in Alzheimer’s disease. Journal of Neuroscience, 30(20), 6873–6881. doi:10.1523/JNEUROSCI.0519-10.2010.CrossRefPubMed

Wei, H., Chadman, K. K., McCloskey, D. P., Sheikh, A. M., Malik, M., Brown, W. T., et al. (2012). Brain IL-6 elevation causes neuronal circuitry imbalances and mediates autism-like behaviors. Biochimica et Biophysica Acta, 1822(6), 831–842. doi:10.1016/j.bbadis.2012.01.011.CrossRefPubMed

Wen, Y., Yu, W. H., Maloney, B., Bailey, J., Ma, J., Marie, I., et al. (2008). Transcriptional regulation of beta-secretase by p25/cdk5 leads to enhanced amyloidogenic processing. Neuron, 57(5), 680–690. doi:10.1016/j.neuron.2008.02.024.CrossRefPubMedPubMedCentral

Yoo, K. Y., & Park, S. Y. (2012). Terpenoids as potential anti-Alzheimer’s disease therapeutics. Molecules, 17(3), 3524–3538. doi:10.3390/molecules17033524.CrossRefPubMed

Yu, L., Chen, C., Wang, L. F., Kuang, X., Liu, K., Zhang, H., et al. (2013). Neuroprotective effect of kaempferol glycosides against brain injury and neuroinflammation by inhibiting the activation of NF-kappaB and STAT3 in transient focal stroke. PLoS ONE, 8(2), e55839. doi:10.1371/journal.pone.0055839.CrossRefPubMedPubMedCentral

Yun, H. M., Jin, P., Park, K. R., Hwang, J., Jeong, H. S., Kim, E. C., et al. (2016). Thiacremonone potentiates anti-oxidant effects to improve memory dysfunction in an APP/PS1 transgenic mice model. Molecular Neurobiology, 53(4), 2409–2420. doi:10.1007/s12035-015-9208-0.CrossRefPubMed

Zheng, J., Son, D. J., Lee, H. L., Lee, H. P., Kim, T. H., Joo, J. H., et al. (2017). (E)-2-methoxy-4-(3-(4-methoxyphenyl)prop-1-en-1-yl)phenol suppresses ovarian cancer cell growth via inhibition of ERK and STAT3. Molecular Carcinogenesis. doi:10.1002/mc.22648.

Zhu, H. T., Bian, C., Yuan, J. C., Chu, W. H., Xiang, X., Chen, F., et al. (2014). Curcumin attenuates acute inflammatory injury by inhibiting the TLR4/MyD88/NF-kappaB signaling pathway in experimental traumatic brain injury. Journal of Neuroinflammation, 11, 59. doi:10.1186/1742-2094-11-59.CrossRefPubMedPubMedCentral

Title: (E)-2-Methoxy-4-(3-(4-methoxyphenyl) prop-1-en-1-yl) Phenol Ameliorates LPS-Mediated Memory Impairment by Inhibition of STAT3 Pathway
Authors: Ji Yeon Choi
Chul Ju Hwang
Do Yeon Lee
Sun Mi Gu
Hee Pom Lee
Dong Young Choi
Ki Wan Oh
Sang-Bae Han
Jin Tae Hong
Publication date: 01-12-2017
Publisher: Springer US
Published in: NeuroMolecular Medicine / Issue 4/2017
Print ISSN: 1535-1084
Electronic ISSN: 1559-1174
DOI: https://doi.org/10.1007/s12017-017-8469-3

At a glance: The STEP trials

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(E)-2-Methoxy-4-(3-(4-methoxyphenyl) prop-1-en-1-yl) Phenol Ameliorates LPS-Mediated Memory Impairment by Inhibition of STAT3 Pathway

Abstract

At a glance: The STEP trials

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Abstract

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