Honokiol, a compound with aspicy odor extracted from variousMagnolia species worldwide, including those native to theSoutheastern United States andMexico, can readily cross the blood-brain and cerebrospinal fluid barriers, making it a highly bioavailable and potentially effective therapeutic agent. Honokiol is a small, hydrophobicneolignanbiphenol structurally similar topropofol that can be purified efficiently from its isomermagnolol using advanced chromatography techniques such as magnolol acetonide protection followed by flash chromatography or high-capacity high-speed countercurrent chromatography.
Because of its physical properties, honokiol can readily cross theblood brain barrier and the blood-cerebrospinal fluid barrier.[1][3] As a result, honokiol is a potentially potent therapy with highbioavailability.
Honokiol belongs to a class of neolignan biphenols. As a polyphenol it is relatively small and can interact with cell membrane proteins through intermolecular interactions likehydrogen bonding,hydrophobic interactions, oraromatic pi orbital co-valency.[1] It is hydrophobic and readily dissolved in lipids. It is structurally similar topropofol.[1]
There are several methods for purifying and isolating honokiol. In nature, honokiol exists with its structural isomermagnolol, which differs from honokiol only by the position of onehydroxyl group. Because of the very similar properties of magnolol and honokiol, purification has often been limited to aHPLC orelectromigration. However, methods developed in 2006 by workers in the lab ofJack L. Arbiser, took advantage of the proximity of the phenolic hydroxyl groups in magnolol, which form a protectablediol, to generate amagnololacetonide (Figure 1), with a subsequent simple purification viaflash chromatography oversilica.[4]
Figure 1
Magnolol and Honokiol are normally inseparable. Honokiol is easily separable from the protected magnolol acetonide
Additionally a rapid separation approach was published in theJournal of Chromatography A in 2007. The process uses high-capacity high-speedcountercurrent chromatography (high-capacity HSCCC).[5] Through this method honokiol can be separated and purified to above 98% purity with a high yield in under an hour.
Extracts from the bark or seed cones of theMagnolia tree have been widely used in traditional medicine in China, Korea, and Japan.[2]
Magnolia bark has traditionally been used in Eastern medicine as analgesic and to treat anxiety and mood disorders.[2][6] Intraditional Chinese medicine, magnolia bark is calledHoupu and is most commonly taken from two species,Magnolia obovata andMagnolia officinalis.[7] Some Chinese traditional formulas containing Houpu include Banxia Houpu Tang (半夏厚朴丸), Xiao Zhengai Tang, Ping Wei San(平胃散) and Shenmi Tang.[2] JapaneseKampo formulas include, Hange-koboku-to (半夏厚朴湯) and Sai-boku-to (柴朴湯).[2][6]
Research has shown a limited side effect profile for honokiol, and it appears to be well tolerated. However, its antithrombotic effects could cause hemorrhage especially in patients with conditions that would put them at a higher risk likehemophilia orVon Willebrand disease.[1] Additionally, patients already takinganticoagulants should talk to their doctor before taking honokiol supplements. In a 2002 study, researchers induced cell death in fetal rat cortical neurons by directly applying 100μMin vitro.[10]
Honokiol inhibits platelet aggregation in rabbits in a dose-dependent manner, and protects cultured RAEC against oxidized low densitylipoprotein injury. Honokiol significantly increases theprostacyclin metabolite6-keto-PGF1alpha, potentially the key factor in honokiol's antithrombotic activity.[19]
Studies examining honokiol as a protective therapy againstfocal cerebral ischemia-reperfusion injury have identified a number of anti-inflammatory pathways.Neutrophil infiltration of injured tissues can cause further damage and issues with healing. Inin vitro studies, honokiol reducedfMLP (N-formyl-methionyl-leucyl-phenylalanine) and PMA (phorbol-12-myristate-13-acetate) induced neutrophil firm adhesion which is an integral step for infiltration.[1][20] Honokiol inhibitsROS production in neutrophils.[20] Honokiol also blocks inflammatory factor production inglial cells through the inhibition onNF-κB activation.[21][22] This mechanism is believed to suppress production ofNO, tumor necrosis factor-α (TNF-α), andRANTES/CCL5.[21]
Honokiol has also been proposed as anantioxidant. The compound protects againstlipid peroxidation by interfering with ROS production and migration.[20] Accumulation of ROS extracellularly causes macromolecular damage while intracellular accumulation may inducecytokine activation.
One way that honokiol acts as a neuroprotective is through cellular regulation and subsequent inhibition of cytotoxicity. Two mechanisms used to achieve this inhibition are GABAA Modulation and Ca2+ Inhibition. Cytotoxicity inhibition may be the neuroprotective mechanism of honokiol. Honokiol has also been shown to inhibit repetitive firing by blockingglutamate.[23]
It is believed that honokiol acts onGABAA receptors similarly tobenzodiazepines andZ-drugs. However, honokiol has been shown to achieve anxiolysis with fewer motor or cognitive side effects than GABAA receptor agonists such as flurazepam and diazepam. It has been shown that honokiol likely has a higher selectivity for different GABAA receptor subtypes and both magnolol and honokiol showed higher efficacy when acting on receptors containing δ subunits.[1] GABAA receptors control ligand-gated Cl− channels that can help increase seizure thresholds through the influx of chloride anions.Honokiol may also affect the synthesis ofGABA. In a study where mice received seven daily injections of honokiol, researchers observed a mild increase inhippocampal levels ofglutamate decarboxylase (GAD67) an enzyme that catalyzes the synthesis of GABA. However, the increase was within the margin of error for the method used to quantify the protein.[24]
A high concentration of Ca2+ inducesexcitotoxicity which is believed to be the main mechanism behind movement disorders such asALS,Parkinson's disease, and convulsive disorders likeepilepsy. Honokiol disrupts the interfaces post synaptic density protein (PSD95) and neuronal nitric oxide synthase (nNOS).[1] PSD95 and nNOS coupling to the NMDA receptor causes a conformational change responsible for the intracellular influx of Ca2+ which could in turn be a pathway for neurotoxicity. Calcium overloading can also cause damage by over-activation of calcium-stimulated enzymes. Honokiol can reduce calcium influx through inhibition of the fMLP, AlF4−, andthapsigarginG-protein pathways.[20]
Thepharmacokinetics of honokiol have been explored in rats and mice; however, further research must be done in humans.[27] Intravenous delivery of 5–10 mg/kg in rodent models has shown a plasma half-life of around 40–60 minutes while intraperitoneal injections of 250 mg/kg had a plasma half-life around 4–6 hours with maximum plasma concentration occurring between 20 and 30 minutes.[1][28]
Honokiol is most commonly taken orally. There are a number of supplements available containing honokiol. Magnolia tea made from the bark of the tree is also a common delivery method of honokiol.[citation needed] Both Native Americans and Japanese medicine use tea gargles to treat toothaches and sore throats.[29] Because honokiol is highly hydrophobic it must be dissolved in a lipid for many delivery methods. In many current animal studies the compound is dissolved in a lipid emollient and delivered throughintraperitoneal injection. There is ongoing[when?] work developing liposomal emulsions for IV delivery.[27]
^Maruyama, Yuji; Kuribara, H.; Morita, M.; Yuzurihara, M.; Weintraub, S. (1998). "Identification of Magnolol and Honokiol as Anxiolytic Agents in Extracts of Saiboku-to, an Oriental Herbal Medicine".Journal of Natural Products.61 (1):135–138.Bibcode:1998JNAtP..61..135M.doi:10.1021/np9702446.PMID9461663.
^abZhang, Peng; Liu, Xiaoyan; Zhu, Yanjun; Chen, Shizhong; Zhou, Demin; Wang, Yinye (2012). "Honokiol inhibits the inflammatory reaction during cerebral ischemia reperfusion by suppressing NF-κB activation and cytokine production of glial cells".Neuroscience Letters.534:123–7.doi:10.1016/j.neulet.2012.11.052.PMID23262090.S2CID10051483.
^Chao, Louis Kuoping; Liao, Pei-Chun; Ho, Chen-Lung; Wang, Eugene I-Chen; Chuang, Chao-Chin; Chiu, Huan-Wen; Hung, Lang-Bang; Hua, Kuo-Feng (2010). "Anti-Inflammatory Bioactives of Honokiol through Inhibition of Protein Kinase C, Mitogen-Activated Protein Kinase, and the NF-κB Pathway To Reduce LPS-Induced TNFα and NO Expression".Journal of Agricultural and Food Chemistry.58 (6):3472–8.Bibcode:2010JAFC...58.3472C.doi:10.1021/jf904207m.PMID20192217.
^Lin, Yi-Ruu; Chen, Hwei-Hsien; Ko, Chien-Hsin; Chan, Ming-Huan (2006). "Neuroprotective activity of honokiol and magnolol in cerebellar granule cell damage".European Journal of Pharmacology.537 (1–3):64–9.doi:10.1016/j.ejphar.2006.03.035.PMID16631734.
^Ku, Tien-Hsiung; Lee, Yih-Jing; Wang, Su-Jane; Fan, Chen-Hua; Tien, Lu-Tai (2011). "Effect of honokiol on activity of GAD(65) and GAD(67) in the cortex and hippocampus of mice".Phytomedicine.18 (13):1126–9.doi:10.1016/j.phymed.2011.03.007.PMID21561750.
^Lan, KH; Wang, Ying-Wen; Lee, Wei-Ping; Lan, Keng-Li; Tseng, Szu-Han; Hung, Li-Rong; Yen, Sang-Hue; Lin, Han-Chieh; Lee, Shou-Dong (2012). "Multiple effects of Honokiol on the life cycle of hepatitis C virus".Liver International.32 (6):989–97.doi:10.1111/j.1478-3231.2011.02621.x.PMID22098176.S2CID22428079.
^Atanasov, Atanas G.; Wang, Jian N.; Gu, Shi P.; Bu, Jing; Kramer, Matthias P.; Baumgartner, Lisa; Fakhrudin, Nanang; Ladurner, Angela; Malainer, Clemens; Vuorinen, Anna; Noha, Stefan M.; Schwaiger, Stefan; Rollinger, Judith M.; Schuster, Daniela; Stuppner, Hermann; Dirsch, Verena M.; Heiss, Elke H. (2013)."Honokiol: A non-adipogenic PPARγ agonist from nature".Biochimica et Biophysica Acta (BBA) - General Subjects.1830 (10):4813–4819.doi:10.1016/j.bbagen.2013.06.021.PMC3790966.PMID23811337.
^abZheng, J; Tang, Y; Sun, M; Zhao, Y; Li, Q; Zhou, J; Wang, Y (2013). "Characterization, pharmacokinetics, tissue distribution and antitumor activity of honokiol submicron lipid emulsions in tumor-burdened mice".Die Pharmazie.68 (1):41–6.PMID23444779.
^Tsai, Tung-Hu; Chou, Cheng-Jen; Cheng, Fu-Chou; Chen, Chieh-Fu (1994). "Pharmacokinetics of honokiol after intravenous administration in rats assessed using high performance liquid chromatography".Journal of Chromatography B.655 (1):41–5.doi:10.1016/0378-4347(94)00031-x.PMID8061832.
