Expectations of biologically active compounds of the genus Magnolia in biomedicine

Abstract

Magnolia bark is a highly aromatic herbal material obtained from Magnolia officinalis (and other species)of the family Magnoliaceae. In traditional oriental herbal medicine, particularly Chinese medicine, thisdrug is used for many purposes, especially as a mild tranquillizer. The principal active compounds are thebiphenol compounds, magnolol and honokiol, together with other biologically active compounds, whichexert numerous and diverse pharmacological actions. Recent research has produced further evidence forthe mechanism of their anti-inflammatory, anti-oxidant, antimicrobial, and antitumour activities, andthese will be outlined in this review.

Full text

J. Appl. Biomed.
4: 171–178, 2006
ISSN 1214-0287
REVIEW
Expectations of biologically active compounds of the genus
Magnolia in biomedicine
Jiří Patočka 1, Jiří Jakl 2, Anna Strunecká 3
1 Department of Radiology and Toxicology, Faculty of Health and Social Studies, University of South Bohemia,
České Budějovice, Czech Republic
2 Department of Dendrology and Forest Tree Breeding, Faculty of Forestry and Environment of the Czech
University of Agriculture Prague, Czech Republic
3 Department of Physiology and Developmental Biology, Faculty of Science, Charles University, Prague, Czech
Republic
Received 18th July 2006.
Published online 20th October 2006.
Summary
Magnolia bark is a highly aromatic herbal material obtained from Magnolia officinalis (and other species)
of the family Magnoliaceae. In traditional oriental herbal medicine, particularly Chinese medicine, this
drug is used for many purposes, especially as a mild tranquillizer. The principal active compounds are the
biphenol compounds, magnolol and honokiol, together with other biologically active compounds, which
exert numerous and diverse pharmacological actions. Recent research has produced further evidence for
the mechanism of their anti-inflammatory, anti-oxidant, antimicrobial, and antitumour activities, and
these will be outlined in this review.
Keywords: herbal tranquillizer – honokiol – Magnolia – magnolol – obovatol – pharmacology
INTRODUCTION
The genus Magnolia is representative of the ancient
family Magnoliaceae, which has been in existence
since the Tertiary period and consists of 120–130
species. Magnolia bark is a traditional Chinese
medicine, known under the name houpu (from
Magnolia officinalis), that has been used for
Jiří Patočka, Department of Radiology and
Toxicology, Faculty of Health and Social Studies,
University of South Bohemia České Budějovice,
370 01 České Budějovice, Czech Republic
 prof.patocka@gmail.com
 + 0420 494 661 014
thousands of years to treat "stagnation of qi" (low
energy), asthma, digestive problems, and emotional
distress. Magnolia bark is used as a general anti-
stress and anti-anxiety agent. Magnolia has also
been traditionally used to treat breast cancer.
Houpu is an official herb in the Pharmacopoeia
of the People's Republic of China (Pharmacopoeia
1988); the herb is sometimes called chuan houpu,
because it originally came from the Sichuan area of
China. Because traditional Chinese medicine is
becoming increasingly popular in many medical
contexts in other parts of the world, particularly
among patients with cancer, it is important that
recent research demonstrates the relevant
pharmacological effects of various magnolias and
the main pharmacologically active compounds
(Ikeda et al. 2003, Yang et al. 2003). Based on the

Patočka et al.: Expectations of biologically active Magnolia compounds
172
experimental evidence available so far, it seems
likely that Magnolia might be helpful in modern
medicine (Patočka et al. 2002).
BIOLOGY OF MAGNOLIA GENUS
Various magnolias are distinguished by their many
interesting biological features. Current research
raises basic questions as to the definition of the
genus itself. The genus Magnolia consists of about
120-130 species and in the Tertiary period
Magnolias were common in Europe (Azuma et al.
2001, Kim et al. 2001, Hunt et al. 1998). The
majority of Magnolia species grow in the temperate
and tropical zones of southeastern Asia, while other
species grow in the New World. Magnolia
officinalis is not the only recognised source of
magnolia bark; other closely related Asian species
of the section Rytidospermum Spach are also used
in traditional medicine, such as the Japanese
Magnolia obovata 'Wakoboku' (Ito et al. 1982) or
the Chinese Magnolia rostrata. However,
according to the IUCN Red List these are
vulnerable species due to over-harvesting of the
bark and habitat destruction (IUCN 2004).
Magnolia bark was a common ingredient in many
formulas, for example ‘Saiboku-to’ (Maruyana et
al. 1998), ‘Xiao Zhengqi Tang’, ‘Maziren Wan’,
‘Ping Wei San’ and ‘Shenmi Tang’ (Hong-Yen
1980). Some species of Magnolia contain magnolol
and honokiol, and others lignanoids (Hegnauer
1990). The best-known magnolia, Magnolia
grandiflora, is a popular plant utilised in Mexican
traditional medicine (Bastidas Ramírez et. al.
1998). Another form of Magnolia used in medicine
is derived from the flower buds (Hu 2000).
Currently, China produces about 200 tons of
Magnolia bark per year (Jinping 2000).
CHEMISTRY OF MAGNOLIA GENUS
The principal substantial compounds present in
plants of the Magnoliaceae family are different
phenolic compounds and terpenoids. Many
phenolic compounds have been found in the leaves
and bark; for example gallic acid, sennosides A and
B, hesperidin, naringin, syringin, and especially
two neolignan compounds, magnolol (I) and
honokiol (II) (Fig.1). The magnolol content of
magnolia bark is generally in the range of 2-10 %,
while honokiol tends to occur naturally at 1-5
percent in the dried bark. Magnolol and honokiol
are without question pharmacologically the most
meaningful constituents of magnolia bark
(Watanabe et al. 1983, Liu et al. 2006). From the
leaves and bark of M. obovata, the novel biphenyl
ether lignans, obovatol (III) (Fig. 1) and obovatal
were isolated (Ito et al. 1982), together with some
sesquiterpene-neolignans, eudesobovatols A and B,
eudesmagnolol, eudeshonokiols A and B,
clovanemagnolol, and caryolanemagnolol
(Fukuyama et al. 1992).
Fig. 1. Chemical structures of three principal
magnolia lignans: magnolol (I), honokiol (II), and
obovatol (III)
Several monoterpenes and sesquiterpenoids
have been obtained from the leaves of Magnolia
grandiflora L, and, on the basis of spectral
evidence, their structures determined as α- and β-
pinenes, β-eudesmol and bornyl acetate
(Tachikawa 2000), 4α, 6α, 10α-trihydroxy-13-
acetoxyguaia-11-ene and 12,13-diacetoxyguaia-4α,
6α, 10α, 11-tetraol (Yang et al. 1994). In addition,
the known sesquiterpenoid magnograndiolide was
also obtained (Luo et al. 2001). Recently, a new
sesquiterpenoid was obtained from the leaves of
Magnolia delavayi. Its structure was determined as
8β-acetoxy-10α-ethyloxy-guaia-4α, 11-diol (Cao
et al. 2004). A new tricyclo [4.2.0.0(2,8)] octane-
type neolignan, 6-allyl-7- (3,4-dimethoxyphenyl)-
2,3-dimethoxy-8-methyl-tricyclo [4.2.0.0(2,8)] oct-
3-en-5-one, together with 15 known lignan and
neolignan derivatives have been isolated from the
flower buds of Magnolia denudata DESR (Li et al.
2005).

Patočka et al.: Expectations of biologically active Magnolia compounds
173
PHARMACOLOGY OF MAGNOLIA GENUS
Pharmacology of magnolol and honokiol
Magnolol and honokiol, two major phenolic
constituents of Magnolia species which are
abundantly found in the medicinal plants M.
officinalis and M. obovata, show multiple
pharmacological effects (Chen et al. 2006).
Research has elucidated the underlying mechanism
of some of their anti-inflammatory and anti-
oxidative effects. It has been found, for example,
that magnolol is 1000-fold more potent than α-
tocopherol in inhibiting lipid peroxidation in rat
mitochondria (Chang et al. 2003). All active
Magnolia constituents (magnolol, honokiol,
obovatol) showed weak inhibition for inducible NO
synthase (iNOS) activity, but potent inhibition of
iNOS induction and activation of nuclear factor-
kappa B (Matsuda et al. 2001). They also inhibit rat
liver acyl-CoA: cholesterol acyltransferase (ACAT)
with IC50 values of 42, 71, and 86 µM, respectively
(Kwon et al. 1997). Honokiol may protect the
myocardium against ischemic injury and suppress
ventricular arrhythmia during ischemia (Tsai et al.
1999). The mechanism of anxiolytic activity of
various Magnolia extracts has been studied. The
observed antimicrobial activity demonstrates the
potential of Magnolias to be an adjunct in the
treatment of periodontitis (Ho et al. 2001).
Anti-inflammatory activity
The reactive oxygen species produced by
neutrophils contribute to the pathogenesis of focal
cerebral ischemia/reperfusion injury and signal the
inflammatory response. Recently it was shown that
honokiol has a protective effect against focal
cerebral ischemia/reperfusion injury in rats that
paralleled a reduction in reactive oxygen species
production by neutrophils (Liou et al. 2003). To
elucidate the underlying mechanism(s) of the
antioxidative effect of honokiol, peripheral
neutrophils isolated from rats were activated with
phorbol-12-myristate-13-acetate (PMA) or N-
formyl-methionyl-leucyl-phenylalanine (fMLP) in
the presence or absence of honokiol. Liou et al.
(2003) suggested that honokiol inhibited PMA- or
fMLP-induced reactive oxygen species production
by neutrophils by three distinct mechanisms:
(i) honokiol diminished the activity of assembled-
NADPH oxidase, a major reactive oxygen species
producing enzyme in neutrophils by 40% without
interfering with its protein kinase C (PKC)-
dependent assembly; (ii) honokiol inhibited two
other important enzymes for reactive oxygen
species generation in neutrophils, i.e.,
myeloperoxidase and cyclooxygenase, by 20% and
70%, respectively; (iii) honokiol enhanced by 30%,
the activity of glutathione (GSH) peroxidase, an
enzyme that triggers the metabolism of hydrogen
peroxide (H2O2). These data suggested that
honokiol, acting as a potent reactive oxygen species
inhibitor/scavenger, could achieve its focal cerebral
ischemia/reperfusion injury protective effect by
modulating enzyme systems related to reactive
oxygen species production or metabolism,
including NADPH oxidase, myeloperoxidase,
cyclooxygenase, and GSH peroxidase in
neutrophils.
Magnolol is hypothesized to suppress TNF-
alpha production after the endotoxin tolerance
induced by sublethal hemorrhage (SLH) and to
alter or attenuate subsequent endotoxin tolerance
(Liou et al. 2003). Recent results show that the
anti-inflammatory effects of magnolol and
honokiol are mediated through inhibition of the
downstream pathway of MEKK-1 in NF-kappaB
activation signalling (Lee et al. 2005). Plasma and
tissue TNF-alpha increased after sublethal
hemorrhage (SLH); this increase was significantly
suppressed by magnolol. Lipid peroxidation and
SOD activity increased after SLH; magnolol
suppressed the lipid peroxidation but not the SOD
activity. In conclusion, magnolol induces an anti-
inflammatory response and provides early
protection against endotoxin challenge following
SLH; however, magnolol attenuates the protraction
of endotoxin tolerance and inhibits late protection
against endotoxin challenge following SLH (Shih
et al. 2004). The anti-inflammatory and
neuroprotective effects of magnolol have been
demonstrated by other authors (Wang et al. 1995;
Lee et al. 2000, Park et al. 2004, Matsui et al. 2005,
Lin et al. 2006).
Magnolol inhibited mouse hind-paw oedema
induced by carrageenan, and polymyxin B, and
reversed the passive Arthus reaction. The recovered
myeloperoxidase activity in the oedematous paw
was significantly decreased in mice pretreated with
magnolol. Suppression of oedema was
demonstrated not only in normal mice but also in
adrenalectomized animals. Magnolol was less
potent in reducing PGD2 formation in rat mast cells
than indomethacin. Unlike dexamethasone,
magnolol did not increase the liver glycogen level.
The results suggest that the anti-inflammatory
effect of magnolol was neither mediated by
glucocorticoid activity, nor through releasing
steroid hormones from the adrenal gland. It is
proposed that the action of magnolol is dependent
on reducing the level of eicosanoid mediators
(Wang et al. 1992).
Antioxidant activity
Magnolol induces apoptosis in rat vascular smooth
muscle cells (VSMCs) via the mitochondrial death
pathway. This effect is mediated through down-
regulation of Bcl-2 protein levels, both in vivo and
in vitro. Magnolol thus shows potential as a novel
therapeutic agent for the treatment of
atherosclerosis and re-stenosis (Chen et al. 2003).

Patočka et al.: Expectations of biologically active Magnolia compounds
174
Magnolol suppressed thromboxane B2 (TXB2)
and leukotriene B4 (LTB4) formation in A23187-
stimulated rat neutrophils. Maximum inhibition
was obtained with about 10 µM magnolol.
Magnolol was more effective in the inhibition of
cyclooxygenase (COX) activity than in the
inhibition of 5-lipoxygenase (5-LO) activity, as
assessed by means of enzyme activity
determination in vitro and COX and 5-LO
metabolic capacity analyses in vivo. Magnolol
alone stimulated cytosolic phospholipase A2
(cPLA2) phosphorylation and the translocation of
5-LO and cPLA2 to the membrane, and evoked
arachidonic acid (AA) release. These results
indicate that magnolol inhibits the formation of
prostaglandins and leukotrienes in A23187-
stimulated rat neutrophils, probably through a
direct blockade of COX and 5-LO activities (Hsu et
al. 2004). The hepatoprotective effects of honokiol
and magnolol on oxidative stress induced by tert-
butylhydroperoxide were probably the result of
their antioxidant activity. Honokiol and magnolol
also had a protective effect against D-
galactosamine-induced hepatotoxicity, which was
used as an alternate model to oxidative stress,
acting by inhibiting intracellular GSH depletion
(Park et al. 2003). Recently a novel synthetically
prepared magnolol derivative, 3,3'-bis-allyl-
magnolol, was developed as a potential antioxidant
for certain diseases (Li et al. 2003).
Anxiolytic activity
The bark of the root and stem of various Magnolia
species has been used in Traditional Chinese
Medicine to treat a variety of disorders including
anxiety and nervous disturbances. Honokiol and
magnolol have been identified as modulators of the
GABA(A) receptors in vitro (Squires et al. 1999,
Ai et al. 2001). The possible selectivity of honokiol
and magnolol on GABA(A) receptor subtypes was
demonstrated in a study using 3H-muscimol and
3H-flunitrazepam binding assays on various rat
brain membrane preparations and human
recombinant GABA(A) receptor subunit
combinations. These results indicate that honokiol
and magnolol have some selectivity on different
GABA(A) receptor subtypes, which could be
responsible for the reported in vivo effects of these
two compounds.
The anxiolytic effect of honokiol, evaluated by
means of an elevated plus-maze test, was at least
5000 times more potent than the compound
preparation ‘Saiboku-to’ when mice were treated
orally for seven days, and was comparable with the
effect of benzodiazepines (Maruyama et al. 1998).
Kuribara et al. (1999) compared the anxiolytic
potentials of honokiol and water extracts of three
Magnolia samples using an improved elevated
plus-maze in mice. Their results suggest that
honokiol is the major constituent responsible for
the observed anxiolytic effect of the water extract
of Magnolia, and that the other components,
including magnolol, scarcely influence the effect of
honokiol.
Antiarrhythmic activity
Tsai et al. (1996) demonstrated that honokiol may
protect the myocardium against ischemic injury and
suppress ventricular arrhythmia during ischemia
and reperfusion. The experimental ventricular
arrhythmia induced by coronary ligation of rats for
30 min were significantly reduced after intravenous
pre-treatment (15 min before coronary ligation)
with 10-7 g/kg magnolol or 10-7 g/kg honokiol.
However, the antiarrhythmic effect of magnolol or
honokiol could be abolished with the pre-treatment
of 1 mg/kg nitric oxide inhibitor (L-NAME), but
not with pre-treatment of 100 mg/kg aspirin. The
abolishment of the beneficial effects of magnolol
and honokiol on the myocardium by L-NAME,
rather than aspirin, suggests the involvement of an
increased nitric oxide synthesis in the protection
offered by magnolol and honokiol against
arrhythmia during myocardial ischemia (Tsai et al.
1999).
Antimicrobial activity
Three phenolic constituents of Magnolia
grandiflora L. were shown to possess significant
antimicrobial activity using an agar well diffusion
assay. Magnolol, honokiol, and 3.5'-diallyl-2'-
hydroxy-4-methoxybiphenyl exhibited significant
activity against Gram-positive and acid-fast
bacteria and fungi (Clark et al. 1981). Magnolol
and honokiol have an antimicrobial activity against
numerous microorganisms such as Porphyromonas
gingivalis, Prevotella intermedia, Actinobacillus
actinomycetemcomitans, Capnocytophaga
gingivalis, Veillonella disper, Micrococcus luteus,
and Bacillus subtilis (Chang et al. 1998, Ho et al.
2001).
Both biphenolic compounds, although less
potent than chlorhexidine, show a significant
antimicrobial activity against these
microorganisms, and a relatively low cytotoxic
effect on human gingival cells. Thus, it is suggested
that magnolol and honokiol might have a potential
therapeutic use as a safe oral antiseptic for the
prevention and the treatment of periodontal disease
(Chang et al. 1998, Ho et al. 2001). Magnolol from
Magnolia officinalis (cortex) potently inhibited the
growth of Helicobacter pylori (Bae et al. 1998).
Antitumor activity
The neolignans magnolol and honokiol have been
reported to inhibit the growth of several tumour cell
lines, both in vitro and in vivo (Kong et al. 2005).
Magnolol has been reported to have anticancer
activity (Lin et al. 2001). Magnolol at very low
concentrations inhibited DNA synthesis and

Patočka et al.: Expectations of biologically active Magnolia compounds
175
decreased cell number in cultured human cancer
cells (COLO-205 and Hep-G2) in a dose-dependent
manner, but not in human untransformed cells such
as keratinocytes, fibroblasts, and human umbilical
vein endothelial cells (HUVEC). Magnolol was not
cytotoxic at these concentrations and this indicates
that it may have an inhibitory effect on cell
proliferation in the subculture cancer cell lines (Lin
et al. 2002). Magnolol possesses the ability to
inhibit tumour growth due to the induction of
apoptosis with the activation of caspases (Ikeda and
Nagase 2002) and a strong antimetastatic effect
due to its ability to inhibit tumour cell invasion
(Ikeda et al. 2003). Magnolol induced the reduction
of mitochondrial transmembrane potential and the
release of cytochrome C into the cytoplasm.
Magnolol-induced apoptotic signalling appears to
be carried out through mitochondrial alternations to
caspase-9, and then downstream effector caspases
are activated sequentially. Magnolol could be thus
a potentially effective drug for the adjunctive
treatment of leukaemia, with low toxicity to normal
blood cells (Zhong et al. 2003). These findings
warrant further investigation.
Recently Fong et al., (2005) discovered that
magnolol and honokiol enhance HL-60 cell
differentiation initiated by low doses of 1.25-
dihydroxyvitamin D3 (VD3) and all-trans-retinoic
acid (ATRA). Cells expressing membrane
differentiation markers CD11b and CD14 were
increased from 4% in the non-treated control to 8-
16% after being treated with 10-30 µM magnolol or
honokiol. It is evident that both these neolignans
are potential differentiation enhancing agents,
which may allow the use of low doses of VD3 and
ATRA in the treatment of acute promyelocytic
leukaemia (Fong et al. 2005). Honokiol
demonstrated weak activity against HIV-1 in
human lymphocytes (Amblard et al. 2006).
Magnolol is a strong 11-beta-hydroxysteroid
dehydrogenase (11-beta-HSD) inhibitor and, like
glycyrrhetinic acid, another 11beta-HSD inhibitor
isolated from licorice, induces apoptosis of murine
thymocytes via the accumulation of corticosterone.
Magnolol has inhibited the enzyme activity in the
kidney (P < 0.0001) and thymus (P < 0.002), while
the activity in the liver was not affected. Blood
concentrations of corticosterone in the magnolol-
treated mice were unexpectedly lower than those in
the control animals (P < 0.002). This means that the
inhibition of 11beta-HSD by magnolol did not
increase the systemic level of corticosterone which
is relevant to thymocyte apoptosis (Horigome et al.
2001).
Pharmacology of obovatol
The biphenyl ether lignan obovatol from
M. obovata (Ito et al. 1982) is slightly different
from magnolol and honokiol not only chemically
but also pharmacologically. Obovatol inhibited the
chitin synthase 2 activity of Saccharomyces
cerevisiae with an IC50 of 38 µM. Its derivative,
tetrahydroobovatol, inhibited chitin synthase 2
activities under the same conditions with an IC50 of
59 µM. These compounds exhibited no inhibitory
activity for chitin synthase 3, and showed less
inhibitory activity for chitin synthase 1 than for
chitin synthase 2 (IC50 > 1 mM). These results
indicated that obovatol and tetrahydroobovatol are
specific inhibitors of chitin synthase 2.
Furthermore, obovatol and tetrahydroobovatol
showed antifungal activities against various
pathogenic fungi, with a particularly strong
inhibitory activity against Cryptococcus
neoformans (MIC 7.8 mg/L). The results indicate
that obovatol and tetrahydroobovatol can
potentially serve as antifungal agents (Hwang et al.
2002).
TOXICOLOGY OF MAGNOLIA GENUS
Magnolia extracts have a two thousand-year-old
safety record for use as a Chinese medicine,
(Bateman et al. 1998), and no significant toxicity or
adverse effects have been reported so far, although
no special chronic toxicological studies with
magnolol, honokiol, and obovatol have been
performed. Very small doses of magnolol and
honokiol appear to be safe and effective for anxiety
and depression. However, large doses may cause a
sedative effect and interact with alcohol, increasing
its effects, so driving or operating dangerous
equipment should be avoided when taking larger
doses of Magnolia extract. Further work on the
toxicology and potential drug interactions of the
constituents of Magnolia need to be performed, in
order that the useful properties of Magnolia species
can be realised.
ACKNOWLEDGEMENT
Preparation of manuscript was supported by A.
Alzheimer Award of Academia Medica Pragensis,
2004.
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