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protection against neuronal cell death caused by oxida-
tive or endoplasmic reticulum (ER) stress (8-10); 3) anti-
tumor activity (11); 4) anti-HIV activity (12); 5) immune
enhancement (13-15); 6) hemagglutinating activity (16,
17); 7) cytotoxicity against cancer cells (18-20); 8) antimi-
crobial activity (21-23); 9) hypoglycemic effects (24); and
10) hypolipidemic effects (25).
Alzheimer’s disease (AD) is the most common form of
dementia, causing memory loss, language deterioration,
impaired ability to manipulate visual information mentally,
poor judgement, confusion, restlessness and mood
swings due to progressive neurodegeneration. It eventu-
ally leads to the loss of cognition, personality and func-
tion. It has been reported that the susceptibility to AD is
closely related to a number of factors, including age,
genes, lack of NGF and excessive accumulation of Aβ.
Conventional treatments for AD only address the symp-
toms, but there is presently no cure. For this reason, heri-
cenones, erinacines and dilinoleoyl-phosphatidylethanol-
amine (DLPE), isolated from H. erinaceum and showing
significant activities in inducing the synthesis of NGF or
protecting against neuronal cell death caused by Aβ, ER
stress or oxidative stress, are attracting great attention
and may be developed into medicinal products or dietary
supplements used for preventing and improving dementia
in general and AD in particular. In this review, we discuss
the isolation and bioactivities of these compounds, and
the possible clinical application of the fungus.
NGF and AD
NGF, one of a family of neurotrophins that induce the
survival and proliferation of neurons, plays an important
role in the repair, regeneration and protection of neurons.
It has been suggested that NGF may be used to treat AD
(26). One report described how a woman with AD experi-
enced improvement in symptoms (including impaired
mental ability) after the administration of NGF directly to
the brain using a catheter (27). However, since NGF is a
protein that cannot pass through the blood-brain barrier
(BBB) and needs to be injected directly into the brain to
be effective, it is a high-risk treatment. A safer therapy for
this disease would be a compound that could be admin-
istered orally, pass through the BBB and so induce NGF
CONTENTS
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
NGF and AD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Hericenones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Erinacines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Bioactivities of hericenones and erinacines . . . . . . . . . . . . . . . .
Aβand AD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DLPE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Bioactivities of DLPE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Preliminary clinical trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Introduction
Hericium erinaceum is an edible and medicinal mush-
room, known in Japan as ‘Yamabushitake’, in China as
‘Hou Tou Gu’ and in Europe and the United States as
‘Lion’s Mane’. It has been demonstrated that H. eri-
naceum exerts important bioactivities, including: 1) the
induction of nerve growth factor (NGF) synthesis (1-7); 2)
inhibition of the cytotoxicity of β-amyloid peptide (Aβ) and
Drugs of the Future 2008, 33(2): 149-155
© 2008 Prous Science, S.A.U. or its licensors. All rights reserved.
CCC: 0377-8282/2008
DOI: 10.1358/dof.2008.033.02.1173290
Review Article
Compounds for dementia from Hericium erinaceum
Hirokazu Kawagishi1,2,*, Cun Zhuang3
1Graduate School of Science and Technology, Shizuoka
University, Shizuoka 422-8529, Japan; 2Department of Applied
Biological Chemistry, Faculty of Agriculture, Shizuoka University,
Shizuoka 422-8529, Japan; 3Bio Research Institute, New
Jersey, USA. *Correspondence: achkawa@agr.shizuoka.ac.jp
Abstract
Our group has been conducting a search for com-
pounds for dementia derived from medicinal mush-
rooms since 1991. A series of benzyl alcohol deriva-
tives (named hericenones C to H), as well as a series
of diterpenoid derivatives (named erinacines A to I)
were isolated from the mushroom Hericium erinaceum.
These compounds significantly induced the synthesis
of nerve growth factor (NGF) in vitro and in vivo. In a
recent study, dilinoleoyl-phosphatidylethanolamine
(DLPE) was isolated from the mushroom and was
found to protect against neuronal cell death caused by
β-amyloid peptide (Aβ) toxicity, endoplasmic reticulum
(ER) stress and oxidative stress. Furthermore, the
results of preliminary clinical trials showed that the
mushroom was effective in patients with dementia in
improving the Functional Independence Measure (FIM)
score or retarding disease progression.
Hericenones
The fruiting bodies of H. erinaceum were extracted
with acetone at room temperature. The acetone extract
was concentrated under reduced pressure, and then frac-
tionated by solvent partition between chloroform and
water. The chloroform-soluble layer was further fraction-
ated and purified by various chromatographies, and six
compounds, named hericenones C to H, were obtained
(1, 2). As shown in Figure 1, hericenones C to H (1-6) are
benzyl alcohol derivatives having simple fatty acids.
synthesis inside the brain. Even if this compound could
not pass through the BBB, it might still be beneficial for
disorders of the peripheral nervous system, since NGF
has a similar effect on neurons in that system.
Based on this concept, a search for natural inducers
of NGF synthesis has been conducted worldwide, and
several compounds with a lower molecular weight were
found to have such bioactivity. Among those bioactive
compounds, hericenones and erinacines from H. eri-
naceum were the first natural compounds and were found
to possess remarkable activities.
2Compounds for dementia from Hericium erinaceum
O
O
OH
O
OH
CH3
OH
CH3
CH3
CH3
H
O
O
O
O
OH
CH3
OH
CH3
CH3
CH3
HH
O
O
O
OH
CH3
OH
CH3
OH
CH3
CH3
H
OO
OH
OH
OH
OH
CH3
CH3
CH3CH3
H
H
H
H
OO
OH
OH
OH
CH3
CH3
CH3CH3
H
H
H
OO
OOH
O
OH
OH
CH3
CH3
CH3
CH3
H
H
H
O
O
O
O
OH
OH
CH3
OH
CH3
CH3
CH3
Na+
O
OH
O
O
CH3
CH3
CH3
CH3CH3
H
O
O
O
O
OH
O
OH
CH3
OH
CH3
CH3
CH3
CH3
H
H
OH
O
O
CH3
CH3O
CH3
CH3
O
H
R
OOCH3O
CH3
CH3
O
CH3
O
R
H
O
O
OH
O
OH
CH3
OH
O
CH3
CH3CH3
CH3
HH
Hericenone C (1) R = palmitoyl
Hericenone D (2) R = stearoyl
Hericenone E (3) R = linoleoyl
Hericenone F (4) R = palmitoyl
Hericenone G (5) R = stearoyl
Hericenone H (6) R = linoleoyl
Erinacine A (7)
Erinacine B (8)Erinacine C (9)Erinacine D (10)
Erinacine E (11)Erinacine F (12)Erinacine G (13)
Erinacine H (14)Erinacine I (15)Erinacine P (16)
Fig. 1. Hericenones and erinacines, inducers of NGF synthesis isolated from Hericium erinaceum.
Bioactivities of hericenones and erinacines
Within the brain, the neuron and astroglia are respon-
sible for NGF production. It has been reported that the
neuron controls NGF synthesis in order to maintain func-
tion in the mature brain, while the astroglia play the same
role when the brain is growing or damaged. Therefore,
primary astroglia derived from rat cerebral cortex were
used in screening for bioactive compounds that induce
the synthesis of NGF. The above compounds were
added to these cells, maintained in a 96-well microplate,
at various concentrations for 24 h, after which NGF
secreted into the culture media was measured by an
enzyme immunoassay (29-32). Hericenones C to E (1-3)
induced the synthesis of NGF in vitro. In the presence of
33 µg/ml of hericenones D (2), E (3) and C (1), the
mouse astroglial cells secreted 23.5 ± 1.0, 13.9 ± 2.1
and 10.8 ± 0.8 pg/ml of NGF, respectively. Hericenone D
was as effective as epinephrine (a potent inducer used
as a positive control) (1). It is interesting to note that the
difference in activity among these compounds was
dependent on the chain length and the double bond of
the fatty acid part. As shown in Figure 3, erinacines A to
G (7-13) were more potent inducers of NGF synthesis
Among these compounds, hericenones F to H (4-6) are
probably formed by cyclization between the phenolic
hydroxyl and the side-chain of hericenones C to E (1-3),
and exist in racemic forms.
Erinacines
The mycelia of H. erinaceum were cultivated in a tank
for 4 weeks, and the mycelia and the culture media were
separated by centrifugation. The mycelia obtained were
extracted with 85% ethanol at room temperature. The
ethanol extract was concentrated under reduced pres-
sure, and then fractionated by solvent partition between
ethyl acetate and water. The ethyl acetate-soluble layer
was further fractionated and purified with various chro-
matographies, and nine compounds, named erinacines A
to I (7-15), were obtained (Fig. 1) (3-6). Erinacines A to I
are diterpenoid derivatives with different chemical struc-
tures from those of the hericenones. In addition, it has
been reported that another compound, named erinacine P
(16), was isolated from the mycelia of H. erinaceum (28).
Erinacine P is considered to be a precursor of erinacines
A (7) and B (8), and can be successfully converted to
these compounds by a biomimetic reaction (Fig. 2).
Drugs Fut 2008, 33(2) 3
CH3
CH3CH3
CH3
O
H
O
OH
OH
OH
O
O
O
CH3
H
CH3
CH3CH3
CH3
H
O
O
OOH
OH
O
H
CH3
CH3CH3
CH3
O
H
O
OH
OH
OH
O
H
Nu+
CH3
CH3CH3
CH3
O
H
O
OH
OH
OH
O
H
CH3
CH3CH3
CH3
O
O
OH
OH
OH
O
H
erinacines E-G
16 8
ii
[1,5]-H shift
7
Path A Path C
elimination
of the acetate
dienolization
eliminati on of 2'-O-
eliminati on
of the nucleophile
Path B
i or ii
1,4-addition of 2'-OH
eliminati on of AcO -1,4-addition of [Nu]
eliminati on of 2'-O -
(ii)
Fig. 2. Biogenesis for the erinacine family.
ibotenic acid-induced dementia and rats with artificially
induced cerebrovascular dementia. The results suggest
that these compounds were beneficial in maintaining
memory and improving learning skills in these models
(manuscript in preparation).
Aβand AD
Neuronal cell death is an essential feature of neu-
rodegenerative diseases, including AD, Parkinson’s dis-
ease and the prion diseases. It has been reported that
many types of neuronal cell death are related to Aβ(34),
glutamate (35) and nitric oxide (36).
Aβ, a major component of senile plaques, is consid-
ered to cause the inflammation and degradation of neu-
rons due to ER and oxidative stress and lead to AD fol-
lowing its deposition in the brain. AD has a long
sympotom-free incubation period but Is basically irre-
versible when diagnosed in advanced stages. Therefore,
an effective way to reduce the risk of AD may be the daily
intake of foods or dietary supplements that can inhibit the
toxicity of Aβ(37, 38).
DLPE
The fruiting bodies of H. erinaceum were extracted
with 85% ethanol and then acetone. The extracts were
combined and concentrated under reduced pressure. The
concentrated extract was partitioned between chloroform
and water. The chloroform-soluble layer was concentrat-
ed and then fractionated by chromatography on a silica
gel column to obtain 14 fractions. Fraction 10, which
showed the highest activity in the screening test, was fur-
ther purified by various chromatographies and DLPE was
obtained (10).
than epinephrine, and erinacine C (9) showed the
strongest activity (3-5, 33).
A further study was conducted in vivo in rats to exam-
ine the effects of erinacine A (7) on the production of cate-
cholamines and NGF in the various regions of the central
nervous system (7). Twenty newborn rats were divided
equally into two groups. The control group was given 5%
ethanol in phosphate-buffered saline (PBS) (10 ml/kg p.o.),
and the treatment group was given 5% ethanol in buffer
with erinacine A (8 mg/kg p.o.) for 4 weeks. After the last
administration, the rats were decapitated under anesthesia
and the catecholamine and NGF content was measured in
the following brain regions: olfactory bulb, locus coeruleus,
hippocampus and cerebral cortex. The results are shown in
Figure 4. In the locus coeruleus, dopamine levels were
unchanged in both groups, but the levels of its metabolites
3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic
acid (HVA) were significantly higher in the erinacine A-
treated group than in the control group. Levels of nora-
drenaline (NA), which is mainly produced in the locus
coeruleus, significantly differed between control rats and
those treated with erinacine A. There was no significant dif-
ference in the contents of 5-hydroxyindoleacetic acid
(5-HIAA), 5-hydroxytryptamine (5-HT) and 5-HT + 5-HIAA
(5-HIs) The effects of erinacine A on NGF synthesis in var-
ious brain regions are shown in Figure 5. In the locus
coeruleus and hippocampus, the NGF content of the eri-
nacine A-treated group was much higher than that of the
control group. There was no significant difference between
the groups in the NGF content of the olfactory bulb and
cerebral cortex. The above findings suggest that erinacine
A may enhance the synthesis of NGF by increasing the
secretion of noradrenaline and catecholamines (7).
Another in vivo study was performed to investigate the
effects of hericenone C and erinacine A in rats with
4Compounds for dementia from Hericium erinaceum
Fig. 3. Effects of erinacines A to G on NGF synthesis. PC (positive control): epinephrine.
tively, compared to 8.88 ± 4.64% for controls. In particu-
lar, the cell viability increased markedly to 67.0 ± 2.32%
and 92.4 ± 1.63% upon the addition of 50 and 150 ng/ml
of DLPE (Fig. 6). In the caspase-12 activation (a marker
of the ER stress signal) assay, tunicamycin clearly
reduced the amount of procaspase-12, whereas DLPE
and HE extract inhibited the decrease in procaspase-12
or caspase-12 activation (10). Also, HE extract was
shown to protect neuronal cells from Aβ- or oxidative
stress-induced cell death (8, 9).
Preliminary clinical trials
A clinical trial was conducted to investigate the effects
of H. erinaceum on dementia in a rehabilitative hospital in
Japan, with 50 patients in the treatment group (average
age: 75.0 years) and 50 patients used as controls (average
age: 77.2 years) (39). All patients were suffering from cere-
brovascular disease, degenerative orthopedic disease,
Parkinson’s disease, spinocerebellar degeneration, dia-
betic neuropathy, spinal cord injury or disuse syndrome.
Seven of the patients in the experimental group suffered
from AD or cerebrovascular dementia. The patients in this
group received 5 g/day of the lyophilized mushroom in
their soup for a 6-month period. All patients were evaluat-
ed before and after the treatment period for their
Functional Independence Measure (FIM), an international
evaluation standard of independence in physical capabili-
ties (eating, dressing, evacuating, walking, bathing/show-
ering, etc.) and perceptive capabilities (understanding,
expression, communication, problem solving, memory).
After 6 months of taking the mushroom, 6 of 7 dementia
patients showed improvement in their perceptual capaci-
ties, and all 7 had improvement in their overall FIM score
(Fig. 7). In particular, 3 bedridden patients were able to get
up for meals after the administration (39).
Bioactivities of DLPE
The protective effect of DLPE against ER stress-
induced neuronal cell death was investigated. Neuro2a
cells were cultured in a 96-well plate at a cell density of
5,000 cells/well. After 1 day of culture, the cells were cul-
tured in Dulbecco’s modified Eagles medium (DMEM)
without PBS, and 0.5 µg/ml of tunicamycin (an inducer of
ER stress) and varying concentrations of DLPE or HE
extract (chloroform-soluble fraction of H. erinaceum) were
applied to the medium. The cells were incubated for 24 h
and the cell viability was measured by the 3-(4,5-
dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bro-
mide (MTT) assay. The results showed that the cell via-
bility in cultures exposed to 10 and 100 ng/ml of HE
extracts were 64.8 ± 10.56% and 76.9 ± 5.65%, respec-
Drugs Fut 2008, 33(2) 5
Fig. 4. Monoamine content in the locus coeruleus of rats fed eri-
nacine A. *p< 0.05.
Fig. 5. Effects of erinacine A on NGF synthesis in the brain of
rats. OLB, olfactory bulb; LC, locus coeruleus, Hip, hippocam-
pus; CC, cerebral cotex. *p< 0.05.
activities in the induction of NGF synthesis or the protec-
tion of neuronal cells against Aβ-, ER stress- or oxidative
stress-induced cell death in vitro and in vivo. The results
of preliminary clinical trials indicate that H. erinaceum
appears to be effective for senile dementia, especially
AD.
Bioactivities observed in animal studies in vitro or in
vivo are not always found when applied to humans.
However, in the case of H. erinaceum, the positive results
obtained in the laboratory were confirmed by analogous
results in preliminary clinical trials.
Overall, it appears that H. erinaceum may have great
potential as a medicine or dietary supplement for demen-
tia, especially AD. However, further studies on its mecha-
nism of action and more extensive clinical trials are clear-
ly needed to substantiate the positive results seen so far.
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Conclusions
Several compounds (hericenones, erinacines and
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6Compounds for dementia from Hericium erinaceum
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