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Validation of cyclooxygenase-2 as a direct anti-inflammatory target of 4-O-methylhonokiol in zymosan-induced animal models

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Abstract

4-O-methylhonokiol (MH) is known to inhibit inflammation by partially understood mechanisms. Here, the anti-inflammatory mechanisms of MH were examined using enzymatic, cellular, and animal assays. In enzymatic assays, MH inhibited COX-2 activity with an IC50 of 0.062 μM, and also COX-1 with an IC50 of 2.4 μM. In cellular assays, MH was immunotoxic above 10 μM. At non-toxic concentrations (below 3 μM), MH strongly inhibited COX-2-mediated prostaglandin production with an IC50 of 0.1 μM, whereas did not or slightly affect other functions of B cells, T cells, dendritic cells, and macrophages. In an animal model, MH inhibited the increase in footpad thickness and popliteal lymph node weight in zymosan-injected mice. When analyzed the draining pLNs of zymosan-injected mice on day 5, MH inhibited the overall inflammatory responses. However, MH inhibited cyclooxygenase (COX)-2-mediated prostaglandin production without affecting tumor necrosis factor-α production in inflamed tissues within 6 h after zymosan injection. In summary, our data suggest that COX-2 may be a direct anti-inflammatory target of MH in vitro and in vivo.

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References

  • Ashton, J.C., and M. Glass. 2007. The cannabinoid CB2 receptor as a target for inflammation-dependent neurodegeneration. Current Neuropharmacology 5: 73–80.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bombardier, C., L. Laine, A. Reicin, D. Shapiro, R. Burgos-Vargas, B. Davis, R. Day, M.B. Ferraz, C.J. Hawkey, M.C. Hochberg, T.K. Kvien, T.J. Schnitzer, and V.S. Group. 2000. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. New England Journal of Medicine 343: 1520–1528. 1522 p following 1528.

    Article  CAS  PubMed  Google Scholar 

  • Bresalier, R.S., R.S. Sandler, H. Quan, J.A. Bolognese, B. Oxenius, K. Horgan, C. Lines, R. Riddell, D. Morton, A. Lanas, M.A. Konstam, J.A. Baron, and Adenomatous Polyp Prevention on Vioxx Trial, I. 2005. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. New England Journal of Medicine 352: 1092–1102.

    Article  CAS  PubMed  Google Scholar 

  • Chao, L.K., P.C. Liao, C.L. Ho, E.I. Wang, C.C. Chuang, H.W. Chiu, L.B. Hung, and K.F. Hua. 2010. Anti-inflammatory bioactivities of honokiol through inhibition of protein kinase C, mitogen-activated protein kinase, and the NF-kappaB pathway to reduce LPS-induced TNFalpha and NO expression. Journal of Agriculture and Food Chemistry 58: 3472–3478.

    Article  CAS  Google Scholar 

  • Choi, I.S., Y.J. Lee, D.Y. Choi, Y.K. Lee, Y.H. Lee, K.H. Kim, Y.H. Kim, Y.H. Jeon, E.H. Kim, S.B. Han, J.K. Jung, Y.P. Yun, K.W. Oh, D.Y. Hwang, and J.T. Hong. 2011. 4-O-methylhonokiol attenuated memory impairment through modulation of oxidative damage of enzymes involving amyloid-beta generation and accumulation in a mouse model of Alzheimer’s disease. Journal of Alzheimer’s Disease 27: 127–141.

    PubMed  Google Scholar 

  • Choi, M.S., S.H. Lee, H.S. Cho, Y. Kim, Y.P. Yun, H.Y. Jung, J.K. Jung, B.C. Lee, H.B. Pyo, and J.T. Hong. 2007. Inhibitory effect of obovatol on nitric oxide production and activation of NF-kappaB/MAP kinases in lipopolysaccharide-treated RAW 264.7cells. European Journal of Pharmacology 556: 181–189.

    Article  CAS  PubMed  Google Scholar 

  • Coxib, Traditional, N.T.C, N. Bhala, J. Emberson, A. Merhi, S. Abramson, N. Arber, J.A. Baron, C. Bombardier, C. Cannon, M.E. Farkouh, G.A. Fitzgerald, P. Goss, H. Halls, E. Hawk, C. Hawkey, C. Hennekens, M. Hochberg, L.E. Holland, P.M. Kearney, L. Laine, A. Lanas, P. Lance, A. Laupacis, J. Oates, C. Patrono, T.J. Schnitzer, S. Solomon, P. Tugwell, K. Wilson, J. Wittes, and C. Baigent. 2013. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet 382: 769–779.

    Article  Google Scholar 

  • Fitzgerald, G.A., and C. Patrono. 2001. The coxibs, selective inhibitors of cyclooxygenase-2. New England Journal of Medicine 345: 433–442.

    Article  CAS  PubMed  Google Scholar 

  • Fu, Y., B. Liu, N. Zhang, Z. Liu, D. Liang, F. Li, Y. Cao, X. Feng, X. Zhang, and Z. Yang. 2013. Magnolol inhibits lipopolysaccharide-induced inflammatory response by interfering with TLR4 mediated NF-kappaB and MAPKs signaling pathways. Journal of Ethnopharmacology 145: 193–199.

    Article  CAS  PubMed  Google Scholar 

  • Fuchs, A., V. Rempel, and C.E. Muller. 2013. The natural product magnolol as a lead structure for the development of potent cannabinoid receptor agonists. PLoS One 8: e77739.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Han, H., J.K. Jung, S.B. Han, S.Y. Nam, K.W. Oh, and J.T. Hong. 2011. Anxiolytic-like effects of 4-O-methylhonokiol isolated from Magnolia officinalis through enhancement of GABAergic transmission and chloride influx. Journal of Medicinal Food 14: 724–731.

    Article  CAS  PubMed  Google Scholar 

  • Han, S.B., C.W. Lee, Y.D. Yoon, J.H. Lee, J.S. Kang, K.H. Lee, W.K. Yoon, K. Lee, S.K. Park, and H.M. Kim. 2005. Prevention of arthritic inflammation using an oriental herbal combination BDX-1 isolated from Achyranthes bidentata and Atractylodes japonica. Archives of Pharmacal Research 28: 902–908.

    Article  CAS  PubMed  Google Scholar 

  • Ibrahim, T., J.M. Cunha, K. Madi, L.M. Da Fonseca, S.S. Costa, and V.L. Goncalves Koatz. 2002. Immunomodulatory and anti-inflammatory effects of Kalanchoe brasiliensis. International Immunopharmacology 2: 875–883.

    Article  CAS  PubMed  Google Scholar 

  • Inotai, A., B. Hanko, and A. Meszaros. 2010. Trends in the non-steroidal anti-inflammatory drug market in six Central-Eastern European countries based on retail information. Pharmacoepidemiology and Drug Safety 19: 183–190.

    Article  PubMed  Google Scholar 

  • Kim, H.S., J.Y. Kim, H.S. Ryu, H.G. Park, Y.O. Kim, J.S. Kang, H.M. Kim, J.T. Hong, Y. Kim, and S.B. Han. 2010. Induction of dendritic cell maturation by beta-glucan isolated from Sparassis crispa. International Immunopharmacology 10: 1284–1294.

    Article  CAS  PubMed  Google Scholar 

  • Kim, H.S., B.R. Shin, H.K. Lee, Y.S. Park, Q. Liu, S.Y. Kim, M.K. Lee, J.T. Hong, Y. Kim, and S.B. Han. 2013a. Dendritic cell activation by polysaccharide isolated from Angelica dahurica. Food and Chemical Toxicology 55: 241–247.

    Article  CAS  PubMed  Google Scholar 

  • Kim, J.Y., H.S. Kim, Y.J. Kim, H.K. Lee, J.S. Kim, J.S. Kang, J.T. Hong, Y. Kim, B.Y. Hwang, and S.B. Han. 2013b. Effusanin C inhibits inflammatory responses via blocking NF-kappaB and MAPK signaling in monocytes. International Immunopharmacology 15: 84–88.

    Article  CAS  PubMed  Google Scholar 

  • Kim, J.Y., H.S. Kim, Y.J. Kim, H.K. Lee, J.S. Kim, J.S. Kang, J.T. Hong, Y. Kim, B.Y. Hwang, and S.B. Han. 2013c. Inhibition of TAK1 by kamebakaurin in dendritic cells. International Immunopharmacology 15: 138–143.

    Article  CAS  PubMed  Google Scholar 

  • Lee, B., J.H. Kwak, S.W. Huang, J.Y. Jang, S. Lim, Y.S. Kwak, K. Lee, H.S. Kim, S.B. Han, J.T. Hong, H. Lee, S. Song, S.Y. Seo, and J.K. Jung. 2012a. Design and synthesis of 4-O-methylhonokiol analogs as inhibitors of cyclooxygenase-2 (COX-2) and PGF(1) production. Bioorganic and Medicinal Chemistry 20: 2860–2868.

    Article  CAS  PubMed  Google Scholar 

  • Lee, H.K., H.S. Kim, Y.J. Kim, J.S. Kim, Y.S. Park, J.S. Kang, D.Y. Yuk, J.T. Hong, Y. Kim, and S.B. Han. 2013a. Sophoricoside isolated from Sophora japonica ameliorates contact dermatitis by inhibiting NF-kappaB signaling in B cells. International Immunopharmacology 15: 467–473.

    Article  CAS  PubMed  Google Scholar 

  • Lee, N.J., J.H. Oh, J.O. Ban, J.H. Shim, H.P. Lee, J.K. Jung, B.W. Ahn, D.Y. Yoon, S.B. Han, Y.W. Ham, and J.T. Hong. 2013b. 4-O-methylhonokiol, a PPARgamma agonist, inhibits prostate tumour growth: p21-mediated suppression of NF-kappaB activity. British Journal of Pharmacology 168: 1133–1145.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Lee, Y.J., D.Y. Choi, I.S. Choi, K.H. Kim, Y.H. Kim, H.M. Kim, K. Lee, W.G. Cho, J.K. Jung, S.B. Han, J.Y. Han, S.Y. Nam, Y.W. Yun, J.H. Jeong, K.W. Oh, and J.T. Hong. 2012b. 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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Lee, Y.J., D.Y. Choi, Y.K. Lee, Y.M. Lee, S.B. Han, Y.H. Kim, K.H. Kim, S.Y. Nam, B.J. Lee, J.K. Kang, Y.W. Yun, K.W. Oh, and J.T. Hong. 2012c. 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: 677–690.

    CAS  PubMed  Google Scholar 

  • Lee, Y.J., I.S. Choi, M.H. Park, Y.M. Lee, J.K. Song, Y.H. Kim, K.H. Kim, D.Y. Hwang, J.H. Jeong, Y.P. Yun, K.W. Oh, J.K. Jung, S.B. Han, and J.T. Hong. 2011a. 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: 66–77.

    Article  CAS  PubMed  Google Scholar 

  • Lee, Y.K., I.S. Choi, J.O. Ban, H.J. Lee, U.S. Lee, S.B. Han, J.K. Jung, Y.H. Kim, K.H. Kim, K.W. Oh, and J.T. Hong. 2011b. 4-O-methylhonokiol attenuated beta-amyloid-induced memory impairment through reduction of oxidative damages via inactivation of p38 MAP kinase. Journal of Nutritional Biochemistry 22: 476–486.

    Article  CAS  PubMed  Google Scholar 

  • Lee, Y.K., D.Y. Yuk, T.I. Kim, Y.H. Kim, K.T. Kim, K.H. Kim, B.J. Lee, S.Y. Nam, and J.T. Hong. 2009. Protective effect of the ethanol extract of Magnolia officinalis and 4-O-methylhonokiol on scopolamine-induced memory impairment and the inhibition of acetylcholinesterase activity. Journal of Natural Medicines 63: 274–282.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Lunn, C.A. 2010. Updating the chemistry and biology of cannabinoid CB2 receptor-specific inverse agonists. Current Topics in Medicinal Chemistry 10: 768–778.

    Article  CAS  PubMed  Google Scholar 

  • Nimmo, A.J., and R. Vink. 2009. Recent patents in CNS drug discovery: the management of inflammation in the central nervous system. Recent Patents on CNS Drug Discovery 4: 86–95.

    Article  CAS  PubMed  Google Scholar 

  • Ochi, T., Y. Ohkubo, and S. Mutoh. 2003. Role of cyclooxygenase-2, but not cyclooxygenase-1, on type II collagen-induced arthritis in DBA/1 J mice. Biochemical Pharmacology 66: 1055–1060.

    Article  CAS  PubMed  Google Scholar 

  • Oh, J.H., J.O. Ban, M.C. Cho, M. Jo, J.K. Jung, B. Ahn, D.Y. Yoon, S.B. Han, and J.T. Hong. 2012. 4-O-methylhonokiol inhibits colon tumor growth via p21-mediated suppression of NF-kappaB activity. Journal of Nutritional Biochemistry 23: 706–715.

    Article  CAS  PubMed  Google Scholar 

  • Oh, J.H., L.L. Kang, J.O. Ban, Y.H. Kim, K.H. Kim, S.B. Han, and J.T. Hong. 2009. Anti-inflammatory effect of 4-O-methylhonokiol, compound isolated from Magnolia officinalis through inhibition of NF-kappaB. Chemico–Biological Interactions 180: 506–514.

    Article  CAS  PubMed  Google Scholar 

  • Oitate, M., T. Hirota, T. Murai, S. Miura, and T. Ikeda. 2007. Covalent binding of rofecoxib, but not other cyclooxygenase-2 inhibitors, to allysine aldehyde in elastin of human aorta. Drug Metabolism and Disposition 35: 1846–1852.

    Article  CAS  PubMed  Google Scholar 

  • Oku, H., and K. Ishiguro. 2002. Cyclooxygenase-2 inhibitory 1,4-naphthoquinones from Impatiens balsamina L. Biological and Pharmaceutical Bulletin 25: 658–660.

    Article  CAS  PubMed  Google Scholar 

  • Ozbay, L.A., J. Stubbe, B. Jespersen, and B.L. Jensen. 2013. The effects of calcineurin inhibitors on prostanoid synthesis: a randomized cross-over study in healthy humans. Transplant International 26: 131–137.

    Article  PubMed  Google Scholar 

  • Park, S.H., M.S. Kyeong, Y. Hwang, S.Y. Ryu, S.B. Han, and Y. Kim. 2012. Inhibition of LPS binding to MD-2 co-receptor for suppressing TLR4-mediated expression of inflammatory cytokine by 1-dehydro-10-gingerdione from dietary ginger. Biochemical and Biophysical Research Communications 419: 735–740.

    Article  CAS  PubMed  Google Scholar 

  • Penning, T.D., J.J. Talley, S.R. Bertenshaw, J.S. Carter, P.W. Collins, S. Docter, M.J. Graneto, L.F. Lee, J.W. Malecha, J.M. Miyashiro, R.S. Rogers, D.J. Rogier, S.S. Yu, E.G. Andersongd Burton, J.N. Cogburn, S.A. Gregory, C.M. Koboldt, W.E. Perkins, K. Seibert, A.W. Veenhuizen, Y.Y. Zhang, and P.C. Isakson. 1997. Synthesis and biological evaluation of the 1,5-diarylpyrazole class of cyclooxygenase-2 inhibitors: identification of 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benze nesulfonamide (SC-58635, celecoxib). Journal of Medicinal Chemistry 40: 1347–1365.

    Article  CAS  PubMed  Google Scholar 

  • Pertwee, R.G., A.C. Howlett, M.E. Abood, S.P. Alexander, V. Di Marzo, M.R. Elphick, P.J. Greasley, H.S. Hansen, G. Kunos, K. Mackie, R. Mechoulam, and R.A. Ross. 2010. International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB(1) and CB(2). Pharmacological Reviews 62: 588–631.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Schuehly, W., J.M. Paredes, J. Kleyer, A. Huefner, S. Anavi-Goffer, S. Raduner, K.H. Altmann, and J. Gertsch. 2011. Mechanisms of osteoclastogenesis inhibition by a novel class of biphenyl-type cannabinoid CB(2) receptor inverse agonists. Chemistry and Biology 18: 1053–1064.

    Article  CAS  PubMed  Google Scholar 

  • Schuhly, W., A. Hufner, E.M. Pferschy-Wenzig, E. Prettner, M. Adams, A. Bodensieck, O. Kunert, A. Oluwemimo, E. Haslinger, and R. Bauer. 2009a. Design and synthesis of ten biphenyl-neolignan derivatives and their in vitro inhibitory potency against cyclooxygenase-1/2 activity and 5-lipoxygenase-mediated LTB4-formation. Bioorganic and Medicinal Chemistry 17: 4459–4465.

    Article  PubMed  Google Scholar 

  • Schuhly, W., S.I. Khan, and N.H. Fischer. 2009b. Neolignans from North American Magnolia species with cyclooxygenase 2 inhibitory activity. Inflammopharmacology 17: 106–110.

    Article  CAS  PubMed  Google Scholar 

  • Seo, K.H., D.Y. Lee, D.S. Lee, J.H. Park, R.H. Jeong, Y.J. Jung, S. Shrestha, I.S. Chung, G.S. Kim, Y.C. Kim, and N.I. Baek. 2013. Neolignans from the fruits of Magnolia obovata and their inhibition effect on NO production in LPS-induced RAW 264.7 cells. Planta Medica 79: 1335–1340.

    Article  CAS  PubMed  Google Scholar 

  • Son, H.J., H.J. Lee, H.S. Yun-Choi, and J.H. Ryu. 2000. Inhibitors of nitric oxide synthesis and TNF-alpha expression from Magnolia obovata in activated macrophages. Planta Medica 66: 469–471.

    Article  CAS  PubMed  Google Scholar 

  • Taferner, B., W. Schuehly, A. Huefner, I. Baburin, K. Wiesner, G.F. Ecker, and S. Hering. 2011. Modulation of GABAA-receptors by honokiol and derivatives: subtype selectivity and structure-activity relationship. Journal of Medicinal Chemistry 54: 5349–5361.

    Article  CAS  PubMed  Google Scholar 

  • Van Rossum, H.H., F.P. Romijn, N.P. Smit, J.W. De Fijter, and J. Van Pelt. 2009. Everolimus and sirolimus antagonize tacrolimus based calcineurin inhibition via competition for FK-binding protein 12. Biochemical Pharmacology 77: 1206–1212.

    Article  PubMed  Google Scholar 

  • Vassiliou, E., H. Jing, and D. Ganea. 2003. Prostaglandin E2 inhibits TNF production in murine bone marrow-derived dendritic cells. Cellular Immunology 223: 120–132.

    Article  CAS  PubMed  Google Scholar 

  • Vollmer, T.R., A. Stockhausen, and J.Z. Zhang. 2012. Anti-inflammatory effects of mapracorat, a novel selective glucocorticoid receptor agonist, is partially mediated by MAP kinase phosphatase-1 (MKP-1). Journal of Biological Chemistry 287: 35212–35221.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by the grants funded by the Korean government (NRF 2008-0062275 & KIAT 1415126993).

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I have no conflict of interest.

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Authors and Affiliations

  1. College of Pharmacy, Chungbuk National University, 52 Naesoodong, Heungduk, Cheongju, Chungbuk, 361-763, South Korea

    Hyung Sook Kim, Hwa Sun Ryu, Ji Sung Kim, Yong Guk Kim, Hong Kyung Lee, Jae Kyung Jung, Jin Tae Hong, Youngsoo Kim & Sang-Bae Han

  2. College of Pharmacy, Korea University, Sejong, 339-700, South Korea

    Young Shin Kwak & Kiho Lee

  3. College of Pharmacy, Gachon University, Inchon, 406-779, South Korea

    Seung Yong Seo

  4. Korean Research Institute of Bioscience and Biotechnology, Ochang, Chungbuk, 363-883, South Korea

    Jieun Yun & Jong Soon Kang

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Hyung Sook Kim, Hwa Sun Ryu have contributed equally to this work.

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Kim, H.S., Ryu, H.S., Kim, J.S. et al. Validation of cyclooxygenase-2 as a direct anti-inflammatory target of 4-O-methylhonokiol in zymosan-induced animal models. Arch. Pharm. Res. 38, 813–825 (2015). https://doi.org/10.1007/s12272-014-0456-8

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