Magnolol: a Multifunctional Compound Isolated from the Chinese Medicinal Plant Magnolia Officinalis

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European Journal of Integrative Medicine 3 (2011) e317–e324

Review articles Magnolol: A multifunctional compound isolated from the Chinese medicinal plant Magnolia ofﬁcinalis Yung-Hsiang Chen a,b, Po-Hsun Huang c,d, Feng-Yen Lin e, Wen-Chi Chen b, Yuh-Lien Chen f, Wei-Hsian Yin d,g, Kee-Ming Man a,h,i,∗, Po-Len Liu j,∗∗ a Department of Anesthesiology, Tungs’ Taichung MetroHarbor Hospital, Taichung, Taiwan b Graduate Institute of Integrated Medicine, Departments of Urology and Medical Research, China Medical University, Taichung, Taiwan c Division of Cardiology, Taipei Veterans General Hospital, Taipei, Taiwan d Department of Medicine, Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan e Department of Internal Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan f Institute of Anatomy and Cell Biology, National Taiwan University, Taipei, Taiwan g Heart Center, Cheng-Hsin General Hospital, Taipei, Taiwan h Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan i Graduate Institute of Geriatric Medicine, Anhui Medical University, Hefei, China j Department of Respiratory Therapy, College of Medicine, Kaohsiung Medical University, 100, Shih-Chuan 1st Rd., Kaohsiung 80708, Taiwan Received 29 June 2011; received in revised form 6 September 2011; accepted 12 September 2011

Abstract Introduction: Chinese herbs are widely used as important remedies in Oriental integrative medicine. Magnolol is a small polyphenolic molecule with low toxicity that is isolated from the herb genus Magnolia. In preclinical experiments, magnolol was found to have anti-oxidative, anti- inflammatory, anti-tumorigenic, anti-diabetic, anti-microbial, anti-neurodegenerative and anti-depressant properties. Magnolol can also effectively regulate pain control, hormonal signalling, gastrointestinal and uterus modulation as well as provide cardiovascular and liver protective effects. Materials and methods: We briefly conducted PubMed and MEDLINE database reviews for articles that related to magnolol. Results: The major biological mechanisms of action and potential health benefits of magnolol are described. Conclusions: These health benefits of magnolol have provided an increased interest in bringing this herbal compound to the clinic as a novel therapeutic agent. Knowledge of the multiple activities of magnolol can assist with the development of magnolol derivatives and the design of clinical trials that will maximize the potential benefit of magnolol in the patient setting. © 2011 Published by Elsevier GmbH.

Keywords: Antioxidant; Chinese medicine; Inﬂammation; Integrative medicine; Magnolol

Introduction lipid peroxidation [2–5]. Now it is known that magnolol and methanolic extracts of Magnolia exhibit anti-oxidative, anti- Magnolol (Fig. 1) is a polyphenolic compound derived inflammatory, anti-tumorigenic, anti-diabetic, anti-microbial, from Magnolia officinalis, a plant commonly associated with anti-neurodegenerative and anti-depressant properties. These Chinese (Kampo) herbs (Fig. 2) [1]. In the 1990s, it was compounds also regulate hormones, possess positive gastroin- discovered that magnolol could inhibit hydroxyl radicals and testinal and uterus modulatory effects, as well as exhibit cardiovascular and liver protective effects. They can also be effective in controlling pain (Fig. 3) [6]. The knowledge of ∗ Corresponding author at: Tungs’ Taichung MetroHarbor Hospital, 699, Sec. magnolol’s multiple biological activities is encouraging for the 1, Chungchi Rd., Wuchi, Taichung 435, Taiwan. ∗∗ development of magnolol derivatives as well as the design of Corresponding author. clinical trials that will maximize the potential benefit of mag- E-mail addresses: man [email protected] (K.-M. Man), [email protected] (P.-L. Liu). nolol administration in a patient setting.

between hydroxyl radicals and biphenyl compounds including magnolol were estimated [3]. It is thought that chemical mechanisms by which magnolol may function involves a peroxide intermediate followed by a phenolic hydroxyl group attacking the peroxide carbon chain, yielding a pentose or hexose ring and water [7]. Magnolol scavenges hydroxyl radicals that are generated by ultra-violet (UV) irradiation and Fig. 1. The chemical structure of magnolol. inhibits UV-induced mutation in Salmonella [4]. The ability Materials and methods of magnolol to inhibit lipid peroxidation was demonstrated in ex vivo experiments involving rat heart/liver mitochondria The authors searched PubMed and MEDLINE for articles in and human sperm [5,8]. Magnolol is approximately 1000 times English using keywords (alone and in various combinations) in more potent than ␣-tocopherol [5,9] in its ability to inhibit the following categories: lipid peroxidation in the heart mitochondria and 340 times more potent in rat liver mitochondria [8]. With in vivo animal • Magnolia genus related keywords (such as magnolol and hon- studies, it was observed that magnolol protects against small okiol). intestinal, cerebral and hind limb ischemia-reperfusion injuries • Integrative medicine related keywords (complemen- [10–13]. tary/alternative/integrative medicine, traditional Chinese medicine, ethno-botanical survey, herbs, herbal, nutri- Anti-inflammatory and anti-anaphylaxis effects tional/dietary supplements). Previous data shows that magnolol can inhibit inflam- We also performed a manual search of the reference lists in matory enzyme/cytokine production, nuclear factor (NF)-␬B identified publications. Subsequently, one researcher selected activation and leukocyte activation, which indicates that mag- the eligible studies and assessed the relevance of each publica- nolol could have anti-inflammatory properties at clinically tion. In this short review article, the recent findings regarding the achievable concentrations [7]. Magnolol exhibits leukocyte sup- biological effects of the antioxidative molecule magnolol were pression, anti-inflammation and analgesic effects via decreased selected and reviewed. myeloperoxidase activity [14], decreased eicosanoid medi- ator activity [15–17] and decreased leukotriene formation Results [18–23]. Histamine release [21,24], as well as nitric oxide (NO), tumour necrosis factor-␣ (TNF-␣), basic fibroblast growth General antioxidative effects factor, matrix metalloproteinase-1 and interleukin (IL)-4 production are also decreased [25–27]. Magnolol inhibits passive The ability of magnolol to inhibit oxidative stress was first cutaneous anaphylactic reactions [25], skin photoaging [27], demonstrated in vitro. Rate constants for competition reactions neurogenic inflammation, as well as dorsal skin and ear edema [28]. Magnolol is also used traditionally in the treatment of chest tightness and asthma [18–23]. The magnolol-induced inhibi- tions on tracheal smooth muscle contraction and excitability of airway myocytes are due to the inhibition of Ca2+ influx [29,30]. Due to these potential health benefits, there is a def- inite increased interest in utilizing magnolol in the clinic as a novel anti-inflammatory and anti-anaphylaxis agent.

Anti-cancer properties

Konoshima et al. were the first to demonstrate the effect of magnolol against skin cancer in mice [31]. Magnolol can successfully induce apoptosis in tumour cells, including, cultured human hepatoma and colon [32] cancer cells, lung squamous [33] and thyroid [34] carcinoma, melanoma [35,36], fibrosar- coma, monocytic leukaemia [35,37,38] and prostate [39] cancer cells [40]. Li et al. reported that magnolol in human non- small lung cancer cells, induced cell death, not by an apoptotic pathway but rather by autophagy [41]. Magnolol successfully Fig. 2. The flower, leaf, and bark of traditional Chinese medicinal plant Mag- inhibits experimentally induced liver and spleen metastasis nolia officinalis. using lymphoma and melanoma models [42] (Fig. 4). Y.-H. Chen et al. / European Journal of Integrative Medicine 3 (2011) e317–e324 e319

Fig. 3. The medicinal properties of magnolol.

Cardiovascular protection effects Restenosis is a common complication after balloon angio- plasty. A number of cytokines, chemotactic and growth factors Teng et al. were the first to demonstrate, in rabbit, that mag- may be involved. Previous studies illustrated that magnolol nolol can inhibit the aggregation of platelet-rich plasma that was treatment significantly inhibited Cu2+-induced low density induced by collagen and arachidonic acid [43]. It was concluded lipoprotein (LDL) oxidation in cholesterol-fed rabbits and that the anti-platelet effect of magnolol is due to an inhibitory reduced atheroma formation [48]. These data suggest that mag- effect on thromboxane formation as well as the inhibition of nolol could be a potential novel therapeutic agent for the intracellular calcium mobilization [44]. treatment of restenosis [49]. Vascular smooth muscle cell (VSMC) contraction, prolifer- The adhesion of leukocytes to the vascular endothelium, ation and migration play important roles in the development of mediated by adhesion molecules, is a pivotal early event in cardiovascular diseases [45]. Chen et al. showed that magnolol atherogenesis [50]. Also, due to its anti-inflammatory and induced apoptosis in VSMCs via the mitochondrial apoptotic anti-oxidant properties, magnolol may play important roles in pathway [46]. Wu et al. also showed the apoptotic pathway and the prevention of atherosclerosis and inflammatory responses anti-oxidant effect might mediate the inhibition of cell growth in vivo [51]. More recently, magnolol was found to inhibit car- [47]. diac fibroblast proliferation by interfering with reactive oxygen

Fig. 4. The underling anti-cancer mechanisms of magnolol. e320 Y.-H. Chen et al. / European Journal of Integrative Medicine 3 (2011) e317–e324

Fig. 5. The cardiovascular protection effects of magnolol. species generation [52]. These results provide a therapeutic Depressant and anti-depressant effects basis for the development of magnolol as an anti-oxidative and anti-inflammatory agent for vascular disorders including Watanabe et al. was the first to report that magnolol had atherosclerosis (Fig. 5). centrally acting muscle relaxant activity [57] which produced spindle discharges in sensory and motor cortex electroencephalograms and inhibited midbrain reticular formation- and Anti-neurodegenerative effects hypothalamus-stimulated responses in the neo- and palaeo- cortex electroencephalograms. These results indicated that The protective effect of magnolol against hypoxia-induced magnolol can depress the ascending activating systems as well as cell injury in cortical neuron–astrocyte mixed cultures has been depress the activity of the spinal cord [2,58]. Tsai et al. examined examined. This is the first report demonstrating the protective the possibility that magnolol might elicit its depressant effect effect of magnolol against chemical hypoxic damage or necrotic by modulating central serotonergic activity and concluded that cell death of neurons using cortical neuron–astrocyte mixed cul- the suppression of brain 5-hydroxytryptamine (HT) release by tures [53]. Lee et al. further demonstrated that the protective magnolol was site-specific, and the suppression of cortical 5-HT effects of magnolol against brain damage by potassium cyanide release by magnolol did not occur due to 5-HT autoreceptors at (KCN) or KCN plus lipopolysaccharide in hypoglycemic media the 5-HT terminals [59]. might involve the inhibition of prostaglandin E2 (PGE2) produc- On the other hand, Nakazawa et al. indicated that magnolol tion; however, inhibition of nitric oxide generation did not appear acted similar to other anti-depressants [60]. Recently, Xu et al. to play a major role in this protective response [54]. Lin et al. also reported on the anti-depressant-like effects of oral adminis- reported that the neuroprotective effects of magnolol might be tration of a honokiol and magnolol mixture in well-validated related to its anti-oxidative actions. By antagonizing the toxicity models of depression in rodents [61]. These results suggested induced by excitatory amino acids, this herbal compound could that the synergistic anti-depressant-like effects of magnolol potentially be used to treat neurodegenerative diseases [55]. might be mediated simultaneously by the regulation of sero- Magnolol was identified as a modulator of ␥-aminobutyric tonergic and gastroenteric system functions. These findings also acid (GABA)A receptor subtypes, due to its ability to selectively provided a potential pharmacological basis for the clinical anti- interact with GABAA receptors in vitro. Selective interaction depressant application of magnolol. with GABAA receptors provides a mechanism that might explain some of the magnolol regulated in vivo neuroprotective effects [56]. Furthermore, magnolol prevents age-related learning and GI and uterus modulation effects memory impairment by preserving cholinergic neurons in the forebrain, suggesting magnolol may have potential therapeutic The effects of magnolol on muscular contractile responses applications to various neuronal disorders such as Alzheimer’s and intracellular Ca2+ mobilization were investigated in the non- disease. pregnant rat uterus. It was reported by Lu et al. that magnolol Y.-H. Chen et al. / European Journal of Integrative Medicine 3 (2011) e317–e324 e321 might be a putative Ca2+ channel blocker and could be of however, the activity of magnolol was weaker than rosiglita- potential value in the treatment of gynaecological dysfunctions zone. In mature 3T3-L1 adipocytes, magnolol increased basal associated with uterine muscular spasm and dysmenorrhea [62]. and insulin-stimulated glucose uptake. These results suggest that Zhang et al. showed that the inhibitory effects of magnolol on magnolol could improve insulin sensitivity through the activa- the contractility of smooth muscles isolated from gastric fundus tion of PPAR␥ [72]. strips in rats and isolated ileum of guinea pigs was associated with calcium-antagonistic effects that suggest magnolol could Hormone regulation effects improve the gastric emptying of a semi-solid meal and intestinal propulsive activity in mice [63]. The influence of magnolol Hsieh et al. investigated the effects of magnolol on ther- on the contractile activity of isolated colonic (ileum) muscle moregulation and hypothalamic release of 5-HT by in vivo strips in the guinea pig helped elucidate a mechanism by which microdialysis performed in normothermic rats and in febrile rats magnolol might function. Magnolol was found to block receptor- treated with IL-1␤. Their data suggest that magnolol decreases operated cation and voltage dependent Ca2+ channels. Also, body temperature by reducing 5-HT release in the rat hypothala- through the inhibition of the InsP3-sensitive and ryanodine- mus [73]. Tachikawa et al. showed the crude extract of Magnolia sensitive pathways, magnolol can also block calcium release bark inhibited the secretion of catecholamines from bovine from the sarcolemmal membrane [64,65]. These data show that adrenal chromaffin cells that were stimulated by acetylcholine, magnolol exerts therapeutic effects on gastrointestinal disease indicating that the inhibitory effect may be associated with its through relaxation of the GI tract smooth muscles. pharmacological effect on the nervous system [74]. Chen et al. Yang et al. investigated the protective effects of magnolol focused on the identification of the mechanism responsible for on sepsis-induced inflammation and intestinal dysmotility and the effect of magnolol on corticosterone production and found concluded that magnolol prevented sepsis-induced suppression a pathway by which magnolol could induce the expression of of intestinal motility in rats. The potential mechanism for this steroidogenic acute regulatory protein, which is involved in the effect is likely due to the ability of magnolol to modulate self- rate-limiting step in sterodiogenesis [75]. amplified inflammatory events and block oxidative stress in the intestine [66]. Pain control effects

Lin et al. demonstrated that magnolol effectively alleviated Liver protective effects formalin-induced inflammatory pain without motor and cogni- tive side effects, suggesting the use of magnolol in the potential Chiu et al. investigated the ability of magnolol to suppress the treatment of inflammatory pain [76]. The same group also inves- generation of oxygen free radicals and improve the viability of tigated the anti-nociceptive effects of magnolol on animal paw cold-preserved warm-reperfused rat livers. They concluded that licking responses as well as the effect on thermal hyperalgesia, magnolol was an effective antioxidant and suppressed lipid per- which is induced by glutamate receptor agonists in mice. They oxidation in rat liver mitochondria, indicating that in solution, demonstrated that magnolol effectively decreased the inflam- magnolol could be used a protective rinse for transplanted organs matory pain through the inhibition of nociception provoked by against unwanted lipid peroxidation during reperfusion [8]. The NMDA receptor and mGluR5 activation [77]. protective effect of magnolol on the liver was performed in vitro d with tertiary butyl hydroperoxide- and -galactosamine-induced Anti-microbial effects hepatocyte injury as well as in vivo with acetaminophen-induced liver damage in rats. These studies indicate the potential interest Clark et al. were the first to examine the anti-microbial activ- of magnolol in the treatment of toxic acute liver failure [67,68]. ity of magnolol using an agar-well diffusion assay. They found By upregulating the anti-apoptotic Bcl-XL gene and through the that magnolol exhibited significant activity against fungi as well suppression of the Bcl-xS gene, magnolol also induced an anti- as Gram-positive and acid-fast bacteria [78,79], Magnolol is also apoptotic effect in the liver and was protective against ischemia a potent inhibitor of Helicobacter pylori growth [80]. Together and reperfusion (I/R) induced liver injury [69]. Moreover, Yin with the previously known antibacterial activity against Propi- et al. also suggested that Magnolia officinalis might be a promis- onibacterium acnes, it is suggested that magnolol may be used ing candidate for the development of a therapeutic agent for as a possible safe and effective acne-mitigating agent [81]. alcohol-induced liver disease [70]. Discussion Anti-diabetic complication effects Magnolol has multifunctional properties mediated by several Sohn et al. investigated the effect of magnolol on type mechanisms of actions. The development of other polyphenolic 2 diabetic Goto–Kakizaki rats and reported that the use of agents such as curcumin is hindered by poor absorption and rapid magnolol could result in good blood glucose control and pre- excretion [7,82]; however, significant systemic levels of mag- vent or retard the development of diabetic complications [71]. nolol were observed in preclinical models. Magnolol can also Moreover, Choi et al. showed magnolol exhibited binding affin- cross the blood–brain barrier [83,84]. In other words magnolol ity to peroxisome proliferator-activated receptor-␥ (PPAR␥); exhibits a desirable spectrum of bioavailability that is generally e322 Y.-H. Chen et al. / European Journal of Integrative Medicine 3 (2011) e317–e324 not observed with other herbal compounds. Understanding the [8] Chiu JH, Wang JC, Lui WY, Wu CW, Hong CY. 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