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Current Molecular Pharmacology

Author(s): Xiaolin Dai, Long Xie, Kai Liu, Youdan Liang, Yi Cao, Jing Lu, Xian Wang, Xumin Zhang and Xiaofang Li*

DOI: 10.2174/1874467215666220223141101

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The Neuropharmacological Effects of Magnolol and Honokiol: A Review of Signal Pathways and Molecular Mechanisms

Article ID: e230222201374 Pages: 17

  • * (Excluding Mailing and Handling)

Abstract

Magnolol and honokiol are natural lignans with good physiological effects. As the main active substances derived from Magnolia officinalis, their pharmacological activities have attracted extensive attention. It is reported that both of them can cross the blood-brain barrier (BBB) and exert neuroprotective effects through a variety of mechanisms. This suggests that these two ingredients can be used as effective therapeutic compounds to treat a wide range of neurological diseases. This article provides a review of the mechanisms involved in the therapeutic effects of magnolol and honokiol in combating diseases, such as cerebral ischemia, neuroinflammation, Alzheimer's disease, and brain tumors, as well as psychiatric disorders, such as anxiety and depression. Although magnolol and honokiol have the pharmacological effects described above, their clinical potential remains untapped. More research is needed to improve the bioavailability of magnolol and honokiol and perform experiments to examine the therapeutic potential of magnolol and honokiol.

Keywords: Magnolol, honokiol, neuropharmacology, molecular mechanisms, anti-ischaemic, neuritis, neuroma, Alzheimer's disease.

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[1]
Ranaware, A.M.; Banik, K.; Deshpande, V.; Padmavathi, G.; Roy, N.K.; Sethi, G.; Fan, L.; Kumar, A.P.; Kunnumakkara, A.B. Magnolol: A neolignan from the magnolia family for the prevention and treatment of cancer. Int. J. Mol. Sci., 2018, 19(8), E2362.
[http://dx.doi.org/10.3390/ijms19082362] [PMID: 30103472]
[2]
Talarek, S.; Listos, J.; Barreca, D.; Tellone, E.; Sureda, A.; Nabavi, S.F.; Braidy, N.; Nabavi, S.M. Neuroprotective effects of honokiol: From chemistry to medicine. Biofactors, 2017, 43(6), 760-769.
[http://dx.doi.org/10.1002/biof.1385] [PMID: 28817221]
[3]
Bors, W.; Michel, C. Chemistry of the antioxidant effect of polyphenols. Ann. N. Y. Acad. Sci., 2002, 957(1), 57-69.
[http://dx.doi.org/10.1111/j.1749-6632.2002.tb02905.x] [PMID: 12074961]
[4]
Guerra, A.R.; Duarte, M.F.; Duarte, I.F. Targeting tumor metabolism with plant-derived natural products: Emerging trends in cancer therapy. J. Agric. Food Chem., 2018, 66(41), 10663-10685.
[http://dx.doi.org/10.1021/acs.jafc.8b04104] [PMID: 30227704]
[5]
Kunnumakkara, A.B.; Bordoloi, D.; Padmavathi, G.; Monisha, J.; Roy, N.K.; Prasad, S.; Aggarwal, B.B. Curcumin, the golden nutraceutical: Multitargeting for multiple chronic diseases. Br. J. Pharmacol., 2017, 174(11), 1325-1348.
[http://dx.doi.org/10.1111/bph.13621] [PMID: 27638428]
[6]
Quideau, S.; Deffieux, D.; Douat-Casassus, C.; Pouységu, L. Plant polyphenols: Chemical properties, biological activities, and synthesis. Angew. Chem. Int. Ed. Engl., 2011, 50(3), 586-621.
[http://dx.doi.org/10.1002/anie.201000044] [PMID: 21226137]
[7]
Guo, J.W.; Chien, C.C.; Chen, J.H. CYP3A excipient-based microemulsion prolongs the effect of magnolol on ischemia stroke rats. Pharmaceutics, 2020, 12(8), E737.
[http://dx.doi.org/10.3390/pharmaceutics12080737] [PMID: 32764430]
[8]
Han, M.; Yu, X.; Guo, Y.; Wang, Y.; Kuang, H.; Wang, X. Honokiol nanosuspensions: Preparation, increased oral bioavailability and dramatically enhanced biodistribution in the cardio-cerebro-vascular system. Colloids Surf. B Biointerfaces, 2014, 116, 114-120.
[http://dx.doi.org/10.1016/j.colsurfb.2013.12.056] [PMID: 24448177]
[9]
Amorati, R.; Zotova, J.; Baschieri, A.; Valgimigli, L. Antioxidant activity of magnolol and honokiol: Kinetic and mechanistic investigations of their reaction with peroxyl radicals. J. Org. Chem., 2015, 80(21), 10651-10659.
[http://dx.doi.org/10.1021/acs.joc.5b01772] [PMID: 26447942]
[10]
Wang, X.; Duan, X.; Yang, G.; Zhang, X.; Deng, L.; Zheng, H.; Deng, C.; Wen, J.; Wang, N.; Peng, C.; Zhao, X.; Wei, Y.; Chen, L. Honokiol crosses BBB and BCSFB, and inhibits brain tumor growth in rat 9L intracerebral gliosarcoma model and human U251 xenograft glioma model. PLoS One, 2011, 6(4), e18490.
[http://dx.doi.org/10.1371/journal.pone.0018490] [PMID: 21559510]
[11]
Jun-Jun, W.; Xiao-Lei, M.; Jing-Ya, C.; Yong, C. The pharmacokinetics and tissue distribution of honokiol and its metabolites in rats. Eur. J. Drug Metab. Pharmacokinet., 2016, 41(5), 587-594.
[http://dx.doi.org/10.1007/s13318-015-0281-6] [PMID: 25956504]
[12]
Lin, S.P.; Tsai, S.Y.; Lee, Chao P.D.; Chen, Y.C.; Hou, Y.C. Pharmacokinetics, bioavailability, and tissue distribution of magnolol following single and repeated dosing of magnolol to rats. Planta Med., 2011, 77(16), 1800-1805.
[http://dx.doi.org/10.1055/s-0030-1271159] [PMID: 21638244]
[13]
Tsai, T.H.; Chou, C.J.; Chen, C.F. Pharmacokinetics and brain distribution of magnolol in the rat after intravenous bolus injection. J. Pharm. Pharmacol., 1996, 48(1), 57-59.
[http://dx.doi.org/10.1111/j.2042-7158.1996.tb05877.x] [PMID: 8722496]
[14]
Sarrica, A.; Kirika, N.; Romeo, M.; Salmona, M.; Diomede, L. Safety and toxicology of magnolol and honokiol. Planta Med., 2018, 84(16), 1151-1164.
[http://dx.doi.org/10.1055/a-0642-1966] [PMID: 29925102]
[15]
Woodbury, A.; Yu, S.P.; Wei, L.; García, P. Neuro-modulating effects of honokiol: A review. Front. Neurol., 2013, 4, 130.
[http://dx.doi.org/10.3389/fneur.2013.00130] [PMID: 24062717]
[16]
Hou, Y.C.; Chao, P.D.; Chen, S.Y. Honokiol and magnolol increased hippocampal acetylcholine release in freely-moving rats. Am. J. Chin. Med., 2000, 28(3-4), 379-384.
[http://dx.doi.org/10.1142/S0192415X00000441] [PMID: 11154051]
[17]
Matsui, N.; Nakashima, H.; Ushio, Y.; Tada, T.; Shirono, A.; Fukuyama, Y.; Nakade, K.; Zhai, H.; Yasui, Y.; Fukuishi, N.; Akagi, R.; Akagi, M. Neurotrophic effect of magnolol in the hippocampal CA1 region of senescence-accelerated mice (SAMP1). Biol. Pharm. Bull., 2005, 28(9), 1762-1765.
[http://dx.doi.org/10.1248/bpb.28.1762] [PMID: 16141555]
[18]
Lee, Y.K.; Choi, I.S.; Kim, Y.H.; Kim, K.H.; Nam, S.Y.; Yun, Y.W.; Lee, M.S.; Oh, K.W.; Hong, J.T. Neurite outgrowth effect of 4-O-methylhonokiol by induction of neurotrophic factors through ERK activation. Neurochem. Res., 2009, 34(12), 2251-2260.
[http://dx.doi.org/10.1007/s11064-009-0024-7] [PMID: 19557513]
[19]
Fukuyama, Y.; Kubo, M.; Harada, K. The search for, and chemistry and mechanism of, neurotrophic natural products. J. Nat. Med., 2020, 74(4), 648-671.
[http://dx.doi.org/10.1007/s11418-020-01431-8] [PMID: 32643028]
[20]
Skovira, J.W.; Wu, J.; Matyas, J.J.; Kumar, A.; Hanscom, M.; Kabadi, S.V.; Fang, R.; Faden, A.I. Cell cycle inhibition reduces inflammatory responses, neuronal loss, and cognitive deficits induced by hypobaria exposure following traumatic brain injury. J. Neuroinflammation, 2016, 13(1), 299.
[http://dx.doi.org/10.1186/s12974-016-0769-2] [PMID: 27903275]
[21]
Di Giovanni, S.; Movsesyan, V.; Ahmed, F.; Cernak, I.; Schinelli, S.; Stoica, B.; Faden, A.I. Cell cycle inhibition provides neuroprotection and reduces glial proliferation and scar formation after traumatic brain injury. Proc. Natl. Acad. Sci. USA, 2005, 102(23), 8333-8338.
[http://dx.doi.org/10.1073/pnas.0500989102] [PMID: 15923260]
[22]
Kabadi, S.V.; Stoica, B.A.; Hanscom, M.; Loane, D.J.; Kharebava, G.; Murray Ii, M.G.; Cabatbat, R.M.; Faden, A.I. CR8, a selective and potent CDK inhibitor, provides neuroprotection in experimental traumatic brain injury. Neurotherapeutics, 2012, 9(2), 405-421.
[http://dx.doi.org/10.1007/s13311-011-0095-4] [PMID: 22167461]
[23]
Stoica, B.A.; Byrnes, K.R.; Faden, A.I. Cell cycle activation and CNS injury. Neurotox. Res., 2009, 16(3), 221-237.
[http://dx.doi.org/10.1007/s12640-009-9050-0] [PMID: 19526282]
[24]
Giacinti, C.; Giordano, A. RB and cell cycle progression. Oncogene, 2006, 25(38), 5220-5227.
[http://dx.doi.org/10.1038/sj.onc.1209615] [PMID: 16936740]
[25]
Wang, H.; Liao, Z.; Sun, X.; Shi, Q.; Huo, G.; Xie, Y.; Tang, X.; Zhi, X.; Tang, Z. Intravenous administration of Honokiol provides neuroprotection and improves functional recovery after traumatic brain injury through cell cycle inhibition. Neuropharmacology, 2014, 86, 9-21.
[http://dx.doi.org/10.1016/j.neuropharm.2014.06.018] [PMID: 24973706]
[26]
Kou, D.Q.; Jiang, Y.L.; Qin, J.H.; Huang, Y.H. Magnolol attenuates the inflammation and apoptosis through the activation of SIRT1 in experimental stroke rats. Pharmacol. Rep., 2017, 69(4), 642-647.
[http://dx.doi.org/10.1016/j.pharep.2016.12.012] [PMID: 28527875]
[27]
Wang, C.C.; Lin, K.C.; Lin, B.S.; Chio, C.C.; Kuo, J.R. Resuscitation from experimental traumatic brain injury by magnolol therapy. J. Surg. Res., 2013, 184(2), 1045-1052.
[http://dx.doi.org/10.1016/j.jss.2013.04.059] [PMID: 23721932]
[28]
Medzhitov, R. Origin and physiological roles of inflammation. Nature, 2008, 454(7203), 428-435.
[http://dx.doi.org/10.1038/nature07201] [PMID: 18650913]
[29]
Zhou, F.; Jiang, Z.; Yang, B.; Hu, Z. Magnolol exhibits anti-inflammatory and neuroprotective effects in a rat model of intracerebral haemorrhage. Brain Behav. Immun., 2019, 77, 161-167.
[http://dx.doi.org/10.1016/j.bbi.2018.12.018] [PMID: 30597199]
[30]
Glass, C.K.; Saijo, K.; Winner, B.; Marchetto, M.C.; Gage, F.H. Mechanisms underlying inflammation in neurodegeneration. Cell, 2010, 140(6), 918-934.
[http://dx.doi.org/10.1016/j.cell.2010.02.016] [PMID: 20303880]
[31]
Kim, D.J.; Kim, Y.S. Magnolol protects against trimethyltin-induced neuronal damage and glial activation in vitro and in vivo. Neurotoxicology, 2016, 53, 173-185.
[http://dx.doi.org/10.1016/j.neuro.2016.01.001] [PMID: 26756313]
[32]
Fu, Y.; Liu, B.; Zhang, N.; Liu, Z.; Liang, D.; Li, F.; Cao, Y.; Feng, X.; Zhang, X.; Yang, Z. Magnolol inhibits lipopolysaccharide-induced inflammatory response by interfering with TLR4 mediated NF-κB and MAPKs signaling pathways. J. Ethnopharmacol., 2013, 145(1), 193-199.
[http://dx.doi.org/10.1016/j.jep.2012.10.051] [PMID: 23127653]
[33]
Mitchell, J.P. Carmody, R.J. NF-κB and the transcriptional control of inflammation. Int. Rev. Cell Mol. Biol., 2018, 335, 41-84.
[http://dx.doi.org/10.1016/bs.ircmb.2017.07.007] [PMID: 29305014]
[34]
Xian, Y.F.; Ip, S.P.; Mao, Q.Q.; Su, Z.R.; Chen, J.N.; Lai, X.P.; Lin, Z.X. Honokiol improves learning and memory impairments induced by scopolamine in mice. Eur. J. Pharmacol., 2015, 760, 88-95.
[http://dx.doi.org/10.1016/j.ejphar.2015.04.013] [PMID: 25912802]
[35]
Liu, F.C.; Yu, H.P.; Syu, Y.T.; Fang, J.Y.; Lin, C.F.; Chang, S.H.; Lee, Y.T.; Hwang, T.L. Honokiol suppresses formyl peptide-induced human neutrophil activation by blocking formyl peptide receptor 1. Sci. Rep., 2017, 7(1), 6718.
[http://dx.doi.org/10.1038/s41598-017-07131-w] [PMID: 28751674]
[36]
Wang, J.P.; Lin, P.L.; Hsu, M.F.; Chen, C.C. Possible involvement of protein kinase c inhibition in the reduction of phorbol ester-induced neutrophil aggregation by magnolol in the rat. J. Pharm. Pharmacol., 1998, 50(10), 1167-1172.
[http://dx.doi.org/10.1111/j.2042-7158.1998.tb03329.x] [PMID: 9821665]
[37]
Chen, P.J.; Wang, Y.L.; Kuo, L.M.; Lin, C.F.; Chen, C.Y.; Tsai, Y.F.; Shen, J.J.; Hwang, T.L. Honokiol suppresses TNF-α-induced neutrophil adhesion on cerebral endothelial cells by disrupting polyubiquitination and degradation of IκBα Sci. Rep., 2016, 6(1), 26554.
[http://dx.doi.org/10.1038/srep26554] [PMID: 27212040]
[38]
Akagi, M.; Matsui, N.; Akae, H.; Hirashima, N.; Fukuishi, N.; Fukuyama, Y.; Akagi, R. Nonpeptide neurotrophic agents useful in the treatment of neurodegenerative diseases such as Alzheimer’s disease. J. Pharmacol. Sci., 2015, 127(2), 155-163.
[http://dx.doi.org/10.1016/j.jphs.2014.12.015] [PMID: 25727952]
[39]
Lee, Y.J.; Choi, D.Y.; Yun, Y.P.; Han, S.B.; Kim, H.M.; Lee, K.; Choi, S.H.; Yang, M.P.; Jeon, H.S.; Jeong, J.H.; Oh, K.W.; Hong, J.T. Ethanol extract of Magnolia officinalis prevents lipopolysaccharide-induced memory deficiency via its antineuroinflammatory and antiamyloidogenic effects. Phytother. Res., 2013, 27(3), 438-447.
[http://dx.doi.org/10.1002/ptr.4740] [PMID: 22628265]
[40]
Matsui, N.; Takahashi, K.; Takeichi, M.; Kuroshita, T.; Noguchi, K.; Yamazaki, K.; Tagashira, H.; Tsutsui, K.; Okada, H.; Kido, Y.; Yasui, Y.; Fukuishi, N.; Fukuyama, Y.; Akagi, M. Magnolol and honokiol prevent learning and memory impairment and cholinergic deficit in SAMP8 mice. Brain Res., 2009, 1305, 108-117.
[http://dx.doi.org/10.1016/j.brainres.2009.09.107] [PMID: 19815000]
[41]
Kantham, S.; Chan, S.; McColl, G.; Miles, J.A.; Veliyath, S.K.; Deora, G.S.; Dighe, S.N.; Khabbazi, S.; Parat, M.O.; Ross, B.P. Effect of the biphenyl neolignan honokiol on Aβ42-induced toxicity in caenorhabditis elegans, Aβ42 fibrillation, cholinesterase activity, DPPH radicals, and iron(II) chelation. ACS Chem. Neurosci., 2017, 8(9), 1901-1912.
[http://dx.doi.org/10.1021/acschemneuro.7b00071] [PMID: 28650631]
[42]
Hoekstra, J.G.; Hipp, M.J.; Montine, T.J.; Kennedy, S.R. Mitochondrial DNA mutations increase in early stage Alzheimer disease and are inconsistent with oxidative damage. Ann. Neurol., 2016, 80(2), 301-306.
[http://dx.doi.org/10.1002/ana.24709] [PMID: 27315116]
[43]
Lunnon, K.; Keohane, A.; Pidsley, R.; Newhouse, S.; Riddoch-Contreras, J.; Thubron, E.B.; Devall, M.; Soininen, H. Kłoszewska, I.; Mecocci, P.; Tsolaki, M.; Vellas, B.; Schalkwyk, L.; Dobson, R.; Malik, A.N.; Powell, J.; Lovestone, S.; Hodges, A. Mitochondrial genes are altered in blood early in Alzheimer’s disease. Neurobiol. Aging, 2017, 53, 36-47.
[http://dx.doi.org/10.1016/j.neurobiolaging.2016.12.029] [PMID: 28208064]
[44]
Liao, G.; Zhao, Z.; Yang, H.; Li, X. Honokiol ameliorates radiation-induced brain injury via the activation of SIRT3. J. Int. Med. Res., 2020, 48(10), 300060520963993.
[http://dx.doi.org/10.1177/0300060520963993] [PMID: 33081556]
[45]
Li, H.; Jia, J.; Wang, W.; Hou, T.; Tian, Y.; Wu, Q.; Xu, L.; Wei, Y.; Wang, X. Honokiol alleviates cognitive deficits of alzheimer’s disease (PS1V97L) transgenic mice by activating mitochondrial SIRT3. J. Alzheimers Dis., 2018, 64(1), 291-302.
[http://dx.doi.org/10.3233/JAD-180126] [PMID: 29865070]
[46]
Ramesh, S.; Govindarajulu, M.; Lynd, T.; Briggs, G.; Adamek, D.; Jones, E.; Heiner, J.; Majrashi, M.; Moore, T.; Amin, R.; Suppiramaniam, V.; Dhanasekaran, M. SIRT3 activator Honokiol attenuates β-amyloid by modulating amyloidogenic pathway. PLoS One, 2018, 13(1), e0190350.
[http://dx.doi.org/10.1371/journal.pone.0190350] [PMID: 29324783]
[47]
Zheng, J.; Shi, L.; Liang, F.; Xu, W.; Li, T.; Gao, L.; Sun, Z.; Yu, J.; Zhang, J. Sirt3 ameliorates oxidative stress and mitochondrial dysfunction after intracerebral hemorrhage in diabetic rats. Front. Neurosci., 2018, 12, 414.
[http://dx.doi.org/10.3389/fnins.2018.00414] [PMID: 29970985]
[48]
Hampel, H.; Vassar, R.; De Strooper, B.; Hardy, J.; Willem, M.; Singh, N.; Zhou, J.; Yan, R.; Vanmechelen, E.; De Vos, A.; Nisticò, R.; Corbo, M.; Imbimbo, B.P.; Streffer, J.; Voytyuk, I.; Timmers, M.; Tahami Monfared, A.A.; Irizarry, M.; Albala, B.; Koyama, A.; Watanabe, N.; Kimura, T.; Yarenis, L.; Lista, S.; Kramer, L.; Vergallo, A. The β-secretase BACE1 in alzheimer’s disease. Biol. Psychiatry, 2021, 89(8), 745-756.
[http://dx.doi.org/10.1016/j.biopsych.2020.02.001] [PMID: 32223911]
[49]
Xian, Y.F.; Qu, C.; Liu, Y.; Ip, S.P.; Yuan, Q.J.; Yang, W.; Lin, Z.X. Magnolol ameliorates behavioral impairments and neuropathology in a transgenic mouse model of alzheimer’s disease. Oxid. Med. Cell. Longev., 2020, 2020, 5920476.
[http://dx.doi.org/10.1155/2020/5920476] [PMID: 32714487]
[50]
Chen, Y.C.; Wu, J.S.; Tsai, H.D.; Huang, C.Y.; Chen, J.J.; Sun, G.Y.; Lin, T.N. Peroxisome proliferator-activated receptor gamma (PPAR-γ) and neurodegenerative disorders. Mol. Neurobiol., 2012, 46(1), 114-124.
[http://dx.doi.org/10.1007/s12035-012-8259-8] [PMID: 22434581]
[51]
Xie, Z.; Zhao, J.; Wang, H.; Jiang, Y.; Yang, Q.; Fu, Y.; Zeng, H.; Hölscher, C.; Xu, J.; Zhang, Z. Magnolol alleviates Alzheimer’s disease-like pathology in transgenic C. elegans by promoting microglia phagocytosis and the degradation of beta-amyloid through activation of PPAR-γ. Biomed. Pharmacother., 2020, 124, 109886.
[http://dx.doi.org/10.1016/j.biopha.2020.109886] [PMID: 32000045]
[52]
Guha, S.; Johnson, G.V.W.; Nehrke, K. The crosstalk between pathological tau phosphorylation and mitochondrial dysfunction as a key to understanding and treating alzheimer’s disease. Mol. Neurobiol., 2020, 57(12), 5103-5120.
[http://dx.doi.org/10.1007/s12035-020-02084-0] [PMID: 32851560]
[53]
Guo, S.; Xu, J.J.; Wei, N.; Han, J.Y.; Xue, R.; Xu, P.S.; Gao, C.Y. Honokiol attenuates the memory impairments, oxidative stress, neuroinflammation, and GSK-3β activation in vascular dementia rats. J. Alzheimers Dis., 2019, 71(1), 97-108.
[http://dx.doi.org/10.3233/JAD-190324] [PMID: 31322570]
[54]
Bai, Y.; Song, L.; Dai, G.; Xu, M.; Zhu, L.; Zhang, W.; Jing, W.; Ju, W. Antidepressant effects of magnolol in a mouse model of depression induced by chronic corticosterone injection. Steroids, 2018, 135, 73-78.
[http://dx.doi.org/10.1016/j.steroids.2018.03.005] [PMID: 29555480]
[55]
Liyanarachchi, K.; Ross, R.; Debono, M. Human studies on hypothalamo-pituitary-adrenal (HPA) axis. Best Pract. Res. Clin. Endocrinol. Metab., 2017, 31(5), 459-473.
[http://dx.doi.org/10.1016/j.beem.2017.10.011] [PMID: 29223281]
[56]
Wang, C.; Gan, D.; Wu, J.; Liao, M.; Liao, X.; Ai, W. Honokiol exerts antidepressant effects in rats exposed to chronic unpredictable mild stress by regulating brain derived neurotrophic factor level and hypothalamus-pituitary-adrenal axis activity. Neurochem. Res., 2018, 43(8), 1519-1528.
[http://dx.doi.org/10.1007/s11064-018-2566-z] [PMID: 29855846]
[57]
Xu, Q.; Yi, L.T.; Pan, Y.; Wang, X.; Li, Y.C.; Li, J.M.; Wang, C.P.; Kong, L.D. Antidepressant-like effects of the mixture of honokiol and magnolol from the barks of Magnolia officinalis in stressed rodents. Prog. Neuropsychopharmacol. Biol. Psychiatry, 2008, 32(3), 715-725.
[http://dx.doi.org/10.1016/j.pnpbp.2007.11.020] [PMID: 18093712]
[58]
Yi, L.T.; Xu, Q.; Li, Y.C.; Yang, L.; Kong, L.D. Antidepressant-like synergism of extracts from magnolia bark and ginger rhizome alone and in combination in mice. Prog. Neuropsychopharmacol. Biol. Psychiatry, 2009, 33(4), 616-624.
[http://dx.doi.org/10.1016/j.pnpbp.2009.03.001] [PMID: 19285110]
[59]
Xia, Z.; Zhang, C.; Du, Y.; Huang, W.; Xing, Z.; Cao, H.; Nie, K.; Wang, Y.; Xiong, X.; Yang, B. The effect of traditional chinese medicine zhike-houpu herbal pair on depressive behaviors and hippocampal serotonin 1A receptors in rats after chronic unpredictable mild stress. Psychosom. Med., 2019, 81(1), 100-109.
[http://dx.doi.org/10.1097/PSY.0000000000000639] [PMID: 30216226]
[60]
Qiang, L.Q.; Wang, C.P.; Wang, F.M.; Pan, Y.; Yi, L.T.; Zhang, X.; Kong, L.D. Combined administration of the mixture of honokiol and magnolol and ginger oil evokes antidepressant-like synergism in rats. Arch. Pharm. Res., 2009, 32(9), 1281-1292.
[http://dx.doi.org/10.1007/s12272-009-1914-6] [PMID: 19784585]
[61]
Li, L.F.; Lu, J.; Li, X.M.; Xu, C.L.; Deng, J.M.; Qu, R.; Ma, S.P. Antidepressant-like effect of magnolol on BDNF up-regulation and serotonergic system activity in unpredictable chronic mild stress treated rats. Phytother. Res., 2012, 26(8), 1189-1194.
[http://dx.doi.org/10.1002/ptr.3706] [PMID: 22223265]
[62]
Sulakhiya, K.; Kumar, P.; Jangra, A.; Dwivedi, S.; Hazarika, N.K.; Baruah, C.C.; Lahkar, M. Honokiol abrogates lipopolysaccharide-induced depressive like behavior by impeding neuroinflammation and oxido-nitrosative stress in mice. Eur. J. Pharmacol., 2014, 744, 124-131.
[http://dx.doi.org/10.1016/j.ejphar.2014.09.049] [PMID: 25446914]
[63]
Matsui, N.; Akae, H.; Hirashima, N.; Kido, Y.; Tanabe, S.; Koseki, M.; Fukuyama, Y.; Akagi, M. Magnolol enhances hippocampal neurogenesis and exerts antidepressant-like effects in olfactory bulbectomized mice. Phytother. Res., 2016, 30(11), 1856-1861.
[http://dx.doi.org/10.1002/ptr.5695] [PMID: 27510271]
[64]
Zhang, B.; Wang, P.P.; Hu, K.L.; Li, L.N.; Yu, X.; Lu, Y.; Chang, H.S. Antidepressant-like effect and mechanism of action of Honokiol on the mouse Lipopolysaccharide (LPS) depression model. Molecules, 2019, 24(11), E2035.
[http://dx.doi.org/10.3390/molecules24112035] [PMID: 31141940]
[65]
Cheng, J.; Dong, S.; Yi, L.; Geng, D.; Liu, Q. Magnolol abrogates chronic mild stress-induced depressive-like behaviors by inhibiting neuroinflammation and oxidative stress in the prefrontal cortex of mice. Int. Immunopharmacol., 2018, 59, 61-67.
[http://dx.doi.org/10.1016/j.intimp.2018.03.031] [PMID: 29627576]
[66]
Maes, M.; Galecki, P.; Chang, Y.S.; Berk, M. A review on the oxidative and nitrosative stress (O&NS) pathways in major depression and their possible contribution to the (neuro)degenerative processes in that illness. Prog. Neuropsychopharmacol. Biol. Psychiatry, 2011, 35(3), 676-692.
[http://dx.doi.org/10.1016/j.pnpbp.2010.05.004] [PMID: 20471444]
[67]
Miller, A.H.; Maletic, V.; Raison, C.L. Inflammation and its discontents: The role of cytokines in the pathophysiology of major depression. Biol. Psychiatry, 2009, 65(9), 732-741.
[http://dx.doi.org/10.1016/j.biopsych.2008.11.029] [PMID: 19150053]
[68]
Jangra, A.; Dwivedi, S.; Sriram, C.S.; Gurjar, S.S.; Kwatra, M.; Sulakhiya, K.; Baruah, C.C.; Lahkar, M. Honokiol abrogates chronic restraint stress-induced cognitive impairment and depressive-like behaviour by blocking endoplasmic reticulum stress in the hippocampus of mice. Eur. J. Pharmacol., 2016, 770, 25-32.
[http://dx.doi.org/10.1016/j.ejphar.2015.11.047] [PMID: 26638996]
[69]
Li, L.F.; Yang, J.; Ma, S.P.; Qu, R. Magnolol treatment reversed the glial pathology in an unpredictable chronic mild stress-induced rat model of depression. Eur. J. Pharmacol., 2013, 711(1-3), 42-49.
[http://dx.doi.org/10.1016/j.ejphar.2013.04.008] [PMID: 23632393]
[70]
Chio, C.C.; Chen, K.Y.; Chang, C.K.; Chuang, J.Y.; Liu, C.C.; Liu, S.H.; Chen, R.M. Improved effects of honokiol on temozolomide-induced autophagy and apoptosis of drug-sensitive and -tolerant glioma cells. BMC Cancer, 2018, 18(1), 379.
[http://dx.doi.org/10.1186/s12885-018-4267-z] [PMID: 29614990]
[71]
Lin, M.C.; Lee, Y.W.; Tseng, Y.Y.; Lin, Y.W.; Chen, J.T.; Liu, S.H.; Chen, R.M. Honokiol induces autophagic apoptosis in neuroblastoma cells through a P53-dependent pathway. Am. J. Chin. Med., 2019, 47(4), 895-912.
[http://dx.doi.org/10.1142/S0192415X19500472] [PMID: 31091975]
[72]
Yeh, P.S.; Wang, W.; Chang, Y.A.; Lin, C.J.; Wang, J.J.; Chen, R.M. Honokiol induces autophagy of neuroblastoma cells through activating the PI3K/Akt/mTOR and endoplasmic reticular stress/ERK1/2 signaling pathways and suppressing cell migration. Cancer Lett., 2016, 370(1), 66-77.
[http://dx.doi.org/10.1016/j.canlet.2015.08.030] [PMID: 26454217]
[73]
Alzahrani, A.S. PI3K/Akt/mTOR inhibitors in cancer: At the bench and bedside. Semin. Cancer Biol., 2019, 59, 125-132.
[http://dx.doi.org/10.1016/j.semcancer.2019.07.009] [PMID: 31323288]
[74]
Lin, J.W.; Chen, J.T.; Hong, C.Y.; Lin, Y.L.; Wang, K.T.; Yao, C.J.; Lai, G.M.; Chen, R.M. Honokiol traverses the blood-brain barrier and induces apoptosis of neuroblastoma cells via an intrinsic bax-mitochondrion-cytochrome c-caspase protease pathway. Neuro-oncol., 2012, 14(3), 302-314.
[http://dx.doi.org/10.1093/neuonc/nor217] [PMID: 22259050]
[75]
Jeong, J.J.; Lee, J.H.; Chang, K.C.; Kim, H.J. Honokiol exerts an anticancer effect in T98G human glioblastoma cells through the induction of apoptosis and the regulation of adhesion molecules. Int. J. Oncol., 2012, 41(4), 1358-1364.
[http://dx.doi.org/10.3892/ijo.2012.1582] [PMID: 22895699]
[76]
Liang, W-Z.; Chou, C.T.; Chang, H.T.; Cheng, J.S.; Kuo, D.H.; Ko, K.C.; Chiang, N.N.; Wu, R.F.; Shieh, P.; Jan, C.R. The mechanism of honokiol-induced intracellular Ca(2+) rises and apoptosis in human glioblastoma cells. Chem. Biol. Interact., 2014, 221, 13-23.
[http://dx.doi.org/10.1016/j.cbi.2014.07.012] [PMID: 25106108]
[77]
Zhai, H.; Nakade, K.; Mitsumoto, Y.; Fukuyama, Y. Honokiol and magnolol induce Ca2+ mobilization in rat cortical neurons and human neuroblastoma SH-SY5Y cells. Eur. J. Pharmacol., 2003, 474(2-3), 199-204.
[http://dx.doi.org/10.1016/S0014-2999(03)02075-2] [PMID: 12921862]
[78]
Lai, I.C.; Shih, P.H.; Yao, C.J.; Yeh, C.T.; Wang-Peng, J.; Lui, T.N.; Chuang, S.E.; Hu, T.S.; Lai, T.Y.; Lai, G.M. Elimination of cancer stem-like cells and potentiation of temozolomide sensitivity by Honokiol in glioblastoma multiforme cells. PLoS One, 2015, 10(3), e0114830.
[http://dx.doi.org/10.1371/journal.pone.0114830] [PMID: 25763821]
[79]
Wu, Z.; Yu, Q. E2F1-mediated apoptosis as a target of cancer therapy. Curr. Mol. Pharmacol., 2009, 2(2), 149-160.
[http://dx.doi.org/10.2174/1874467210902020149] [PMID: 20021455]
[80]
Chen, L.C.; Liu, Y.C.; Liang, Y.C.; Ho, Y.S.; Lee, W.S. Magnolol inhibits human glioblastoma cell proliferation through upregulation of p21/Cip1. J. Agric. Food Chem., 2009, 57(16), 7331-7337.
[http://dx.doi.org/10.1021/jf901477g] [PMID: 19645506]
[81]
Lin, C.J.; Chang, Y.A.; Lin, Y.L.; Liu, S.H.; Chang, C.K.; Chen, R.M. Preclinical effects of honokiol on treating glioblastoma multiforme via G1 phase arrest and cell apoptosis. Phytomedicine, 2016, 23(5), 517-527.
[http://dx.doi.org/10.1016/j.phymed.2016.02.021] [PMID: 27064011]
[82]
Fan, Y.; Xue, W.; Schachner, M.; Zhao, W. Honokiol eliminates glioma/glioblastoma stem cell-like cells via JAK-STAT3 signaling and inhibits tumor progression by targeting epidermal growth factor receptor. Cancers (Basel), 2018, 11(1), E22.
[http://dx.doi.org/10.3390/cancers11010022] [PMID: 30587839]
[83]
Joo, Y.N.; Eun, S.Y.; Park, S.W.; Lee, J.H.; Chang, K.C.; Kim, H.J. Honokiol inhibits U87MG human glioblastoma cell invasion through endothelial cells by regulating membrane permeability and the epithelial-mesenchymal transition. Int. J. Oncol., 2014, 44(1), 187-194.
[http://dx.doi.org/10.3892/ijo.2013.2178] [PMID: 24247297]
[84]
Cheng, Y.C.; Tsao, M.J.; Chiu, C.Y.; Kan, P.C.; Chen, Y. Magnolol Inhibits Human Glioblastoma Cell Migration by Regulating N-Cadherin. J. Neuropathol. Exp. Neurol., 2018, 77(6), 426-436.
[http://dx.doi.org/10.1093/jnen/nly021] [PMID: 29788114]
[85]
Chandra, A.; Jahangiri, A.; Chen, W.; Nguyen, A.T.; Yagnik, G.; Pereira, M.P.; Jain, S.; Garcia, J.H.; Shah, S.S.; Wadhwa, H.; Joshi, R.S.; Weiss, J.; Wolf, K.J.; Lin, J.G.; Müller, S.; Rick, J.W.; Diaz, A.A.; Gilbert, L.A.; Kumar, S.; Aghi, M.K. Clonal ZEB1-driven mesenchymal transition promotes targetable oncologic antiangiogenic therapy resistance. Cancer Res., 2020, 80(7), 1498-1511.
[http://dx.doi.org/10.1158/0008-5472.CAN-19-1305] [PMID: 32041837]
[86]
Arulselvan, P.; Fard, M.T.; Tan, W.S.; Gothai, S.; Fakurazi, S.; Norhaizan, M.E.; Kumar, S.S. Role of antioxidants and natural products in inflammation. Oxid. Med. Cell. Longev., 2016, 2016, 5276130.
[http://dx.doi.org/10.1155/2016/5276130] [PMID: 27803762]
[87]
Huang, S.Y.; Tai, S.H.; Chang, C.C.; Tu, Y.F.; Chang, C.H.; Lee, E.J. Magnolol protects against ischemic-reperfusion brain damage following oxygen-glucose deprivation and transient focal cerebral ischemia. Int. J. Mol. Med., 2018, 41(4), 2252-2262.
[http://dx.doi.org/10.3892/ijmm.2018.3387] [PMID: 29336466]
[88]
Chen, J.H.; Kuo, H.C.; Lee, K.F.; Tsai, T.H. Magnolol protects neurons against ischemia injury via the downregulation of p38/MAPK, CHOP and nitrotyrosine. Toxicol. Appl. Pharmacol., 2014, 279(3), 294-302.
[http://dx.doi.org/10.1016/j.taap.2014.07.005] [PMID: 25038313]
[89]
Dong, L.; Zhou, S.; Yang, X.; Chen, Q.; He, Y.; Huang, W. Magnolol protects against oxidative stress-mediated neural cell damage by modulating mitochondrial dysfunction and PI3K/Akt signaling. J. Mol. Neurosci., 2013, 50(3), 469-481.
[http://dx.doi.org/10.1007/s12031-013-9964-0] [PMID: 23404573]
[90]
Chen, C.M.; Liu, S.H.; Lin-Shiau, S.Y. Honokiol, a neuroprotectant against mouse cerebral ischaemia, mediated by preserving Na+, K+-ATPase activity and mitochondrial functions. Basic Clin. Pharmacol. Toxicol., 2007, 101(2), 108-116.
[http://dx.doi.org/10.1111/j.1742-7843.2007.00082.x] [PMID: 17651312]
[91]
Hu, Z.; Bian, X.; Liu, X.; Zhu, Y.; Zhang, X.; Chen, S.; Wang, K.; Wang, Y. Honokiol protects brain against ischemia-reperfusion injury in rats through disrupting PSD95-nNOS interaction. Brain Res., 2013, 1491, 204-212.
[http://dx.doi.org/10.1016/j.brainres.2012.11.004] [PMID: 23148950]
[92]
Lee, W.T.; Lin, M.H.; Lee, E.J.; Hung, Y.C.; Tai, S.H.; Chen, H.Y.; Chen, T.Y.; Wu, T.S. Magnolol reduces glutamate-induced neuronal excitotoxicity and protects against permanent focal cerebral ischemia up to 4 hours. PLoS One, 2012, 7(7), e39952.
[http://dx.doi.org/10.1371/journal.pone.0039952] [PMID: 22808077]
[93]
Lin, Y.R.; Chen, H.H.; Ko, C.H.; Chan, M.H. Differential inhibitory effects of honokiol and magnolol on excitatory amino acid-evoked cation signals and NMDA-induced seizures. Neuropharmacology, 2005, 49(4), 542-550.
[http://dx.doi.org/10.1016/j.neuropharm.2005.04.009] [PMID: 15921707]
[94]
Cui, H.S.; Huang, L.S.; Sok, D.E.; Shin, J.; Kwon, B.M.; Youn, U.J.; Bae, K. Protective action of honokiol, administered orally, against oxidative stress in brain of mice challenged with NMDA. Phytomedicine, 2007, 14(10), 696-700.
[http://dx.doi.org/10.1016/j.phymed.2007.03.005] [PMID: 17470388]
[95]
Lin, Y.R.; Chen, H.H.; Ko, C.H.; Chan, M.H. Neuroprotective activity of honokiol and magnolol in cerebellar granule cell damage. Eur. J. Pharmacol., 2006, 537(1-3), 64-69.
[http://dx.doi.org/10.1016/j.ejphar.2006.03.035] [PMID: 16631734]
[96]
Liou, K-T.; Shen, Y.C.; Chen, C.F.; Tsao, C.M.; Tsai, S.K. Honokiol protects rat brain from focal cerebral ischemia-reperfusion injury by inhibiting neutrophil infiltration and reactive oxygen species production. Brain Res., 2003, 992(2), 159-166.
[http://dx.doi.org/10.1016/j.brainres.2003.08.026] [PMID: 14625055]
[97]
Liu, X.; Chen, X.; Zhu, Y.; Wang, K.; Wang, Y. Effect of magnolol on cerebral injury and blood brain barrier dysfunction induced by ischemia-reperfusion in vivo and in vitro. Metab. Brain Dis., 2017, 32(4), 1109-1118.
[http://dx.doi.org/10.1007/s11011-017-0004-6] [PMID: 28378105]
[98]
Harada, S.; Kishimoto, M.; Kobayashi, M.; Nakamoto, K.; Fujita-Hamabe, W.; Chen, H.H.; Chan, M.H.; Tokuyama, S. Honokiol suppresses the development of post-ischemic glucose intolerance and neuronal damage in mice. J. Nat. Med., 2012, 66(4), 591-599.
[http://dx.doi.org/10.1007/s11418-011-0623-x] [PMID: 22261858]
[99]
Vega-García, A.; Santana-Gómez, C.E.; Rocha, L.; Magdaleno-Madrigal, V.M.; Morales-Otal, A.; Buzoianu-Anguiano, V.; Feria-Romero, I.; Orozco-Suárez, S. Magnolia officinalis reduces the long-term effects of the status epilepticus induced by kainic acid in immature rats. Brain Res. Bull., 2019, 149, 156-167.
[http://dx.doi.org/10.1016/j.brainresbull.2019.04.003] [PMID: 30978383]
[100]
Chen, C.R.; Tan, R.; Qu, W.M.; Wu, Z.; Wang, Y.; Urade, Y.; Huang, Z.L. Magnolol, a major bioactive constituent of the bark of Magnolia officinalis, exerts antiepileptic effects via the GABA/benzodiazepine receptor complex in mice. Br. J. Pharmacol., 2011, 164(5), 1534-1546.
[http://dx.doi.org/10.1111/j.1476-5381.2011.01456.x] [PMID: 21518336]
[101]
Ai, J.; Wang, X.; Nielsen, M. Honokiol and magnolol selectively interact with GABAA receptor subtypes in vitro. Pharmacology, 2001, 63(1), 34-41.
[http://dx.doi.org/10.1159/000056110] [PMID: 11408830]
[102]
Qu, W.M.; Yue, X.F.; Sun, Y.; Fan, K.; Chen, C.R.; Hou, Y.P.; Urade, Y.; Huang, Z.L. Honokiol promotes non-rapid eye movement sleep via the benzodiazepine site of the GABA(A) receptor in mice. Br. J. Pharmacol., 2012, 167(3), 587-598.
[http://dx.doi.org/10.1111/j.1476-5381.2012.02010.x] [PMID: 22537192]
[103]
Ma, H.; Kim, C.S.; Ma, Y.; Nam, S.Y.; Kim, D.S.; Woo, S.S.; Hong, J.T.; Oh, K.W. Magnolol enhances pentobarbital-induced sleeping behaviors: Possible involvement of GABAergic systems. Phytother. Res., 2009, 23(9), 1340-1344.
[http://dx.doi.org/10.1002/ptr.2773] [PMID: 19165750]
[104]
Ku, T.H.; Lee, Y.J.; Wang, S.J.; Fan, C.H.; Tien, L.T. Effect of honokiol on activity of GAD(65) and GAD(67) in the cortex and hippocampus of mice. Phytomedicine, 2011, 18(13), 1126-1129.
[http://dx.doi.org/10.1016/j.phymed.2011.03.007] [PMID: 21561750]
[105]
Alexeev, M.; Grosenbaugh, D.K.; Mott, D.D.; Fisher, J.L. The natural products magnolol and honokiol are positive allosteric modulators of both synaptic and extra-synaptic GABA(A) receptors. Neuropharmacology, 2012, 62(8), 2507-2514.
[http://dx.doi.org/10.1016/j.neuropharm.2012.03.002] [PMID: 22445602]
[106]
Sulakhiya, K.; Kumar, P.; Gurjar, S.S.; Barua, C.C.; Hazarika, N.K. Beneficial effect of honokiol on lipopolysaccharide induced anxiety-like behavior and liver damage in mice. Pharmacol. Biochem. Behav., 2015, 132, 79-87.
[http://dx.doi.org/10.1016/j.pbb.2015.02.015] [PMID: 25725264]