Honokiol has been extracted from a number of species of Magnolia native to many regions of the globe. Magnolia grandiflora, which is native to the American South, as well as Mexican species like Magnolia dealbata have been found to be sources of honokiol.[1] Traditionally in Asian medicine, the Magnolia biondii, Magnolia obovata, and Magnolia officinalis are commonly used.[2] The compound itself has a spicy odor.
Because of its physical properties, honokiol can readily cross the
blood brain barrier and the blood-cerebrospinal fluid barrier.[1][3] As a result, honokiol is a potentially potent therapy with high
bioavailability.
Chemistry
Structure
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 like
hydrogen bonding,
hydrophobic interactions, or
aromatic pi orbital co-valency.[1] It is hydrophobic and readily dissolved in lipids. It is structurally similar to
propofol.[1]
Purification
There are several methods for purifying and isolating honokiol. In nature, honokiol exists with its structural isomer
magnolol, which differs from honokiol only by the position of one
hydroxyl group. Because of the very similar properties of magnolol and honokiol, purification has often been limited to a
HPLC or
electromigration. However, methods developed in 2006 by workers in the lab of
Jack L. Arbiser, took advantage of the proximity of the phenolic hydroxyl groups in magnolol, which form a protectable
diol, to generate a
magnololacetonide (Figure 1), with a subsequent simple purification via
flash chromatography over
silica.[4]
Figure 1
Additionally a rapid separation approach was published in the Journal of Chromatography A in 2007. The process uses high-capacity high-speed
countercurrent 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.
History
Traditional medicine
Extracts from the bark or seed cones of the Magnolia 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] In
traditional Chinese medicine, magnolia bark is called Houpu and is most commonly taken from two species, Magnolia obovata and Magnolia 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] Japanese
Kampo 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 like
hemophilia or
Von Willebrand disease.[1] Additionally, patients already taking
anticoagulants 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 100μM in vitro.[10]
Honokiol inhibits platelet aggregation in rabbits in a dose-dependent manner, and protects cultured RAEC against oxidized low density
lipoprotein injury. Honokiol significantly increases the
prostacyclin metabolite
6-keto-PGF1alpha, potentially the key factor in honokiol's antithrombotic activity.[19]
Anti-inflammatory activity
Studies examining honokiol as a protective therapy against
focal 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. In in vitro studies, honokiol reduced
fMLP (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 inhibits
ROS production in neutrophils.[20] Honokiol also blocks inflammatory factor production in
glial cells through the inhibition on
NF-κB activation.[21][22] This mechanism is believed to suppress production of
NO, tumor necrosis factor-α (
TNF-α), and
RANTES/
CCL5.[21]
Antioxidant activity
Honokiol has also been proposed as an
antioxidant. The compound protects against
lipid peroxidation by interfering with ROS production and migration.[20] Accumulation of ROS extracellularly causes macromolecular damage while intracellular accumulation may induce
cytokine activation.
Cytotoxicity inhibition
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 blocking
glutamate.[23]
GABAA modulation
It is believed that honokiol acts on
GABAA receptors similarly to
benzodiazepines and
Z-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 of
GABA. In a study where mice received seven daily injections of honokiol, researchers observed a mild increase in
hippocampal levels of
glutamate 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]
Ca2+ inhibition
A high concentration of Ca2+ induces
excitotoxicity which is believed to be the main mechanism behind movement disorders such as
ALS,
Parkinson's disease, and convulsive disorders like
epilepsy. 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−, and
thapsigarginG-protein pathways.[20]
Honokiol was shown to normalize blood glucose levels and prevent body weight gain in diabetic mice by acting as agonist of
PPARgamma.[26]
Pharmacokinetics
The
pharmacokinetics 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]
Delivery methods
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 through
intraperitoneal 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.
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10.1021/np9702446.
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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.
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^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.
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^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.
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^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.
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^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.
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^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.
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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.
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^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.
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