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International Journal of
Molecular Sciences
Review
Therapeutic Potential of Hericium erinaceus
for Depressive Disorder
Pit Shan Chong 1, Man-Lung Fung 1, Kah Hui Wong 2,* and Lee Wei Lim 1,*
1School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong,
Hong Kong, China; u3005073@connect.hku.hk (P.S.C.); fungml@hku.hk (M.-L.F.)
2Department of Anatomy, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia
*Correspondence: wkahhui@um.edu.my (K.H.W.); drlimleewei@gmail.com (L.W.L.);
Tel.: +603-7967-4729 (K.H.W.); +852-9157-2575 (L.W.L.)
Received: 30 October 2019; Accepted: 20 December 2019; Published: 25 December 2019
Abstract:
Depression is a common and severe neuropsychiatric disorder that is one of the leading
causes of global disease burden. Although various anti-depressants are currently available, their
efficacies are barely adequate and many have side effects. Hericium erinaceus, also known as Lion’s
mane mushroom, has been shown to have various health benefits, including antioxidative, antidiabetic,
anticancer, anti-inflammatory, antimicrobial, antihyperglycemic, and hypolipidemic effects. It has
been used to treat cognitive impairment, Parkinson’s disease, and Alzheimer’s disease. Bioactive
compounds extracted from the mycelia and fruiting bodies of H. erinaceus have been found to promote
the expression of neurotrophic factors that are associated with cell proliferation such as nerve growth
factors. Although antidepressant effects of H. erinaceus have not been validated and compared to
the conventional antidepressants, based on the neurotrophic and neurogenic pathophysiology of
depression, H. erinaceus may be a potential alternative medicine for the treatment of depression.
This article critically reviews the current literature on the potential benefits of H. erinaceus as a treatment
for depressive disorder as well as its mechanisms underlying the antidepressant-like activities.
Keywords:
Hericium erinaceus; Lion’s mane mushroom; depression; antidepressant; mood disorders
1. Introduction
Major depressive disorder, also known as depression, is a common neuropsychiatric disorder that
affects more than 300 million people of all ages [
1
] and is one of the leading causes of global disease
burden [
2
]. The common signs and symptoms of depression include loss of interest in daily activities,
difficulty concentrating and making decisions, fatigue, sleep problems, overeating or appetite loss,
pessimism, hopelessness, persistent sadness, and restlessness [
3
,
4
]. Untreated depression could lead
to suicidal thoughts or suicide attempts [
3
,
5
]. Suicide is the second leading cause of death in young
adults worldwide [1], and approximately 800,000 cases of suicide are reported annually [1].
In the 1950s, pharmacotherapy has become the main treatment for depression since the introduction
of the first generation of antidepressants, which are monoamine oxidase inhibitors (iproniazid)
and tricyclic antidepressants (imipramine) that have been on the market the longest [
6
,
7
]. In the
1980s, the second generation of antidepressants, including selective serotonin reuptake inhibitors
(e.g., fluoxetine, sertraline, and paroxetine) and selective serotonin noradrenaline reuptake inhibitors
(e.g., venlafaxine, duloxetine, and desvenlafaxine), were introduced as a safer class of antidepressants [
6
].
Other antidepressants that are prescribed less often include serotonin 5-HT2C receptor antagonists
(e.g., olanzapine), alpha-2 blockers (e.g., atipamezole), melatonin receptor agonists (e.g., ramelteon),
and selective noradrenaline/dopamine reuptake inhibitors (e.g., nomifensine). Although many types
of antidepressant drugs are available, their overall efficacy is still barely satisfactory [
7
,
8
]. Studies of
Int. J. Mol. Sci. 2020,21, 163; doi:10.3390/ijms21010163 www.mdpi.com/journal/ijms
Int. J. Mol. Sci. 2020,21, 163 2 of 18
antidepressants in adults with moderate or severe depressive disorder revealed that currently available
antidepressants could only relieve symptoms of depression in about 20% of patients [
8
]. Furthermore,
antidepressant medication often needs to be administered continuously for years to prevent relapse [
9
].
Besides, more than 50% of antidepressant users reported that they experienced side effects, including
headaches, dry mouth, anxiety, dizziness, weight gain, decreased interest in sex, as well as a loss
of ability to have an orgasm or an erection [
10
,
11
]. The side effects can often lead to failure in the
administration of antidepressants in depressive patients [12,13].
Herbal medicine can be a cost-effective complementary and alternative medicine for the treatment
of depressive disorders, generally with fewer side effects and limited comparative efficacy to
conventional antidepressants, as well as it is well-tolerated by depressive patients [
14
,
15
]. Mushrooms
are functional foods with high nutritional values and are great sources for novel therapeutic
compounds [
13
,
16
]. Hericium erinaceus is a medicinal-culinary mushroom widely found in East
Asian countries and is commonly known as lion’s mane mushroom, Yamabushitake, or monkey’s
head mushroom [
17
]. Hericium erinaceus has a long history as a medicine [
17
] and has been found to
promote positive nerve and brain health. It has great potential in treating neurological disorders as it
contains neurotrophic compounds that can pass through the blood–brain barrier [
18
,
19
]. Bioactive
compounds extracted from its fruiting body or mycelium (Figure 1) have been demonstrated to possess
antioxidative [
20
], antidiabetic [
21
], anticancer [
22
,
23
], anti-inflammatory [
24
], antimicrobial [
23
],
antihyperglycemic [
25
], and hypolipidemic properties [
26
]. Moreover, H. erinaceus has been used
to treat cognitive impairments [
27
], Alzheimer’s disease [
28
], Parkinson’s disease [
29
], ischemic
stroke [
30
], and presbycusis [
14
]. Recently, the present research on H. erinaceus has been focused on
its antidepressant-like effects for the treatment of depressive disorder [
31
–
33
]. Up to date, no review
concerning the antidepressant effects of H. erinaceus is available. The aim of this review is to critically
review the current literature on the potential antidepressant effects of H. erinaceus as a treatment for
depressive disorder as well as its possible mechanisms underlying the antidepressant-like responses.
Int.J.Mol.Sci.2019,20,x2of18
nomifensine).Althoughmanytypesofantidepressantdrugsareavailable,theiroverallefficacyis
stillbarelysatisfactory[7,8].Studiesofantidepressantsinadultswithmoderateorseveredepressive
disorderrevealedthatcurrentlyavailableantidepressantscouldonlyrelievesymptomsofdepression
inabout20%ofpatients[8].Furthermore,antidepressantmedicationoftenneedstobeadministered
continuouslyforyearstopreventrelapse[9].Besides,morethan50%ofantidepressantusersreported
thattheyexperiencedsideeffects,includingheadaches,drymouth,anxiety,dizziness,weightgain,
decreasedinterestinsex,aswellasalossofabilitytohaveanorgasmoranerection[10,11].Theside
effectscanoftenleadtofailureintheadministrationofantidepressantsindepressivepatients[12,13].
Herbalmedicinecanbeacost‐effectivecomplementaryandalternativemedicineforthe
treatmentofdepressivedisorders,generallywithfewersideeffectsandlimitedcomparativeefficacy
toconventionalantidepressants,aswellasitiswell‐toleratedbydepressivepatients[14,15].
Mushroomsarefunctionalfoodswithhighnutritionalvaluesandaregreatsourcesfornovel
therapeuticcompounds[13,16].Hericiumerinaceusisamedicinal‐culinarymushroomwidelyfound
inEastAsiancountriesandiscommonlyknownaslion’smanemushroom,Yamabushitake,or
monkey’sheadmushroom[17].Hericiumerinaceushasalonghistoryasamedicine[17]andhasbeen
foundtopromotepositivenerveandbrainhealth.Ithasgreatpotentialintreatingneurological
disordersasitcontainsneurotrophiccompoundsthatcanpassthroughtheblood–brainbarrier
[18,19].Bioactivecompoundsextractedfromitsfruitingbodyormycelium(Figure1)havebeen
demonstratedtopossessantioxidative[20],antidiabetic[21],anticancer[22,23],anti‐inflammatory
[24],antimicrobial[23],antihyperglycemic[25],andhypolipidemicproperties[26].Moreover,H.
erinaceushasbeenusedtotreatcognitiveimpairments[27],Alzheimer’sdisease[28],Parkinson’s
disease[29],ischemicstroke[30],andpresbycusis[14].Recently,thepresentresearchonH.erinaceus
hasbeenfocusedonitsantidepressant‐likeeffectsforthetreatmentofdepressivedisorder[31–33].
Uptodate,noreviewconcerningtheantidepressanteffectsofH.erinaceusisavailable.Theaimof
thisreviewistocriticallyreviewthecurrentliteratureonthepotentialantidepressanteffectsofH.
erinaceusasatreatmentfordepressivedisorderaswellasitspossiblemechanismsunderlyingthe
antidepressant‐likeresponses.
Figure1. FruitingbodiescultivatedatthetropicalclimateinMalaysia(A,B)andmycelia(C)of
Hericiumerinaceusgrownonpotatodextroseagar.
Figure 1.
Fruiting bodies cultivated at the tropical climate in Malaysia (
A
,
B
) and mycelia (
C
) of Hericium
erinaceus grown on potato dextrose agar.
Int. J. Mol. Sci. 2020,21, 163 3 of 18
2. Pathophysiology of Depression
Depression is a complex disorder and its etiology is believed to be heterogeneous with many
causes and contributing factors. The pathophysiology of depression is unclear, but it is believed to
involve neurodegeneration and neurobiological changes [
34
]. The following section discusses the
hypotheses of the pathophysiology of depression relating to the therapeutic potential of H. erinaceus.
2.1. Monoamine Hypothesis
The monoamine hypothesis of depression suggests that the major signs and symptoms of
depression are associated with a deficiency in the transmission within the monoamine systems,
including norepinephrine, serotonin, or/and dopamine [
35
,
36
]. The deficiency in the transmission
of monoamine neurotransmitters can be caused by several factors, including the deficiency or
malfunctioning in monoamine precursors, enzymes, receptors, transporters; monoamine synthesis;
high level of monoamine oxidase function; and reduction in exocytosis that are indirectly modulated
by the chemically-gated channels (Figure 2) and clinical
in vivo
findings have provided much evidence
to support the monoamine hypothesis [
35
–
37
]. Reserpine, a drug that was commonly used to treat
schizophrenia and hypertension in the early 1950s, and clinical observations have revealed that the
administration of reserpine depleted presynaptic stores of norepinephrine, serotonin, and dopamine,
which led to a syndrome resembling depression in some patients [
37
–
39
]. Interestingly,
in vivo
studies
found that animals treated with reserpine exhibited depressive-like behavior, which is in line with
clinical findings [
40
,
41
]. In contrast, iproniazid, a drug formulated in the 1950s to treat tuberculosis
was reported to inhibit the metabolic enzyme monoamine oxidase (MAO), leading to increased
extracellular levels of norepinephrine and serotonin in the brain and ultimately resulting in a euphoric
and hyperactive state in a subset of patients [
42
]. Iproniazid and other monoamine oxidase inhibitors
were subsequently found to be effective in improving symptoms of depression, which strongly supports
the monoamine hypothesis of depression. Similarly, antidepressant-like effects were also observed
with the oral administration of H. erinaceus in depressive-like animals, and it was found to restore
expression levels of norepinephrine, serotonin, and dopamine [31].
Int.J.Mol.Sci.2019,20,x3of18
2.PathophysiologyofDepression
Depressionisacomplexdisorderanditsetiologyisbelievedtobeheterogeneouswithmany
causesandcontributingfactors.Thepathophysiologyofdepressionisunclear,butitisbelievedto
involveneurodegenerationandneurobiologicalchanges[34].Thefollowingsectiondiscussesthe
hypothesesofthepathophysiologyofdepressionrelatingtothetherapeuticpotentialofH.erinaceus.
2.1.MonoamineHypothesis
Themonoaminehypothesisofdepressionsuggeststhatthemajorsignsandsymptomsof
depressionareassociatedwithadeficiencyinthetransmissionwithinthemonoaminesystems,
includingnorepinephrine,serotonin,or/anddopamine[35,36].Thedeficiencyinthetransmissionof
monoamineneurotransmitterscanbecausedbyseveralfactors,includingthedeficiencyor
malfunctioninginmonoamineprecursors,enzymes,receptors,transporters;monoaminesynthesis;
highlevelofmonoamineoxidasefunction;andreductioninexocytosisthatareindirectlymodulated
bythechemically‐gatedchannels(Figure2)andclinicalinvivofindingshaveprovidedmuch
evidencetosupportthemonoaminehypothesis[35–37].Reserpine,adrugthatwascommonlyused
totreatschizophreniaandhypertensionintheearly1950s,andclinicalobservationshaverevealed
thattheadministrationofreserpinedepletedpresynapticstoresofnorepinephrine,serotonin,and
dopamine,whichledtoasyndromeresemblingdepressioninsomepatients[37–39].Interestingly,
invivostudiesfoundthatanimalstreatedwithreserpineexhibiteddepressive‐likebehavior,which
isinlinewithclinicalfindings[40,41].Incontrast,iproniazid,adrugformulatedinthe1950stotreat
tuberculosiswasreportedtoinhibitthemetabolicenzymemonoamineoxidase(MAO),leadingto
increasedextracellularlevelsofnorepinephrineandserotonininthebrainandultimatelyresulting
inaeuphoricandhyperactivestateinasubsetofpatients[42].Iproniazidandothermonoamine
oxidaseinhibitorsweresubsequentlyfoundtobeeffectiveinimprovingsymptomsofdepression,
whichstronglysupportsthemonoaminehypothesisofdepression.Similarly,antidepressant‐like
effectswerealsoobservedwiththeoraladministrationofH.erinaceusindepressive‐likeanimals,and
itwasfoundtorestoreexpressionlevelsofnorepinephrine,serotonin,anddopamine[31].
Figure2.Themonoaminehypothesisofdepressionshowingthepotentialfactorsthatcancausea
deficiencyinthetransmissionwithinthemonoaminesystems(createdwithBioRender.com).The
Figure 2.
The monoamine hypothesis of depression showing the potential factors that can cause a
deficiency in the transmission within the monoamine systems (created with BioRender.com). The solid
Int. J. Mol. Sci. 2020,21, 163 4 of 18
arrows indicate the flow of synaptic vesicles containing monoamine neurotransmitters. The dotted
arrows indicate the release or reuptake of the monoamine neurotransmitters across the terminal of
presynaptic neuron.
2.2. Neurotrophic/Neurogenic Hypothesis
The neurotrophic hypothesis of depression involves the neuroplasticity and adaptation of the
nervous system, and the inability of the nervous system to respond or adapt appropriately to aversive
stimuli or stress resulting in depression. Anti-depressant drugs that stimulated appropriate adaptive
responses were able to alleviate the symptoms of depression [
42
]. This hypothesis is associated with
the neurogenic hypothesis that is based on the concept that neurogenesis is negatively regulated during
a stressful condition, which can be positively regulated by antidepressant treatments. Pre-clinical
and clinical findings showed that depression and stress were associated with volumetric decreases in
the hippocampus of adult patients, whereas chronic anti-depressant treatment was able to increase
the proliferation and survival rate of hippocampal neural progenitors [43–46]. The hippocampus is a
neurogenic area in the brain that plays a critical role in learning, memory, and emotion. Neurotrophic
factors are growth factors in the nervous system that play a role in modulating the plasticity of neuronal
cells [
47
,
48
]. Brain-derived neurotrophic factor (BDNF) is one of the neurotrophic factors that are highly
associated with suicidal and depressive behaviors [
49
–
51
]. Although animal studies showed a decrease
in BDNF level was not sufficient to produce depressive-like behaviors, clinical evidence showed
that there was a reduction in BDNF levels with neuronal dysfunction in the brains of patients with
major depressive disorder [
52
–
54
]. Anti-depressant treatments that restored or increased BDNF levels
were able to alleviate symptoms of depression [
51
,
53
,
55
]. BDNF plays a role in activity-dependent
neuroplasticity including cognitive function and memory. Increased BDNF expression level is known
to induce several types of neuroplasticity, including synaptogenesis, adult-neurogenesis, and neuronal
maturation [
56
]. BDNF functions by binding to its receptors, including tropomyosin receptor kinase
B (TrkB) and pan 75 neurotrophin receptor (p75
NTR
), a low-affinity receptor. The binding affinity
of p75
NTR
towards BDNF was found to be increased with less Trk receptors or Trk inactivity [
57
].
This interaction can induce neuronal apoptosis in oligodendrocytes, vascular smooth muscle cells,
and neuronal cells [
47
]. The alteration in BDNF-TrkB signaling is believed to be involved in the
pathogenesis of depression, which could be targeted therapeutically.
2.3. Inflammatory Hypothesis
Depressive disorder was found to link with an increase in expression of various central and
peripheral proinflammatory cytokines, including tumor necrosis factor
α
(TNF-
α
) and interleukin-1,
interleukin-6 (IL-1, IL-6), and interferon-
α
and
γ
[
58
–
61
]. Evidence from an
in vivo
study shows that
the concentration of IL-1 and IL-2 was increased in the rat model of depression subjected to chronic mild
stress [
62
]. Furthermore, animal models of inflammation-associated depression are often generated
through the administration of cytokines or cytokine inducers, including IL-6 and lipopolysaccharide
(LPS) [
63
–
65
]. The administration of IL or LPS, and further exposure to inflammatory induction could
develop depressive-like syndrome and behavior including anorexia, anhedonia, and reduction in
locomotor activity [
66
–
68
]. An
in vivo
study also showed that stress stimulus significantly increases
the level of proinflammatory cytokines including TNF-
α
and IL-18 in the prefrontal cortex and
hippocampus [
69
]. The inflammatory hypothesis is further supported by a clinical trial whereby an
acute increase of depressive-like symptoms was reported in healthy volunteers administered with
LPS [
66
]. Patients with the first episode of depression and those who experiencing recurrent depressive
disorders were reported to have no difference in the concentration of IL-1, IL-6, and IL-10, suggesting
that altered expression of the proinflammatory cytokine is a constant characteristic for depression [
70
].
Additionally, TNF-
α
involves in the onset of the glucocorticoid resistance and activation of the
Int. J. Mol. Sci. 2020,21, 163 5 of 18
hypothalamo–pituitary–adrenocortical axis, induces excessive reuptake of monoamines and stimulates
the indoleamine 2,3-dioxygenase which result in tryptophan and serotonin depletions [
71
,
72
]. Thus,
the inflammatory pathway could be a potential target for the treatment of depression.
3. Hericium erinaceus Ameliorates Depressive-Like Behaviors
3.1. Pre-Clinical Studies
The therapeutic effects of H. erinaceus have been widely studied in several neurological diseases.
However, not many studies have investigated its use in mental disorders. This review summarizes the
behavioral and physiological effects of different H. erinaceus extracts in the studies of depression (Table 1).
Amycenone is an H. erinaceus extract that obtained from the fruiting body through a patented
process, which contains 0.5% hericenone and 6% amyloban [
73
]. In 2015, Yao et al. reported the
antidepressant-like and anti-inflammatory effects of amycenone in an animal model of depression
with LPS-induced inflammation [
33
]. Amycenone was administered orally to mice 60 min before
the intraperitoneal injection of LPS, and behavioral tests were performed 24 h after LPS injection.
They found that acute treatment of 200 mg/kg amycenone significantly reduced the depressive-like
behaviors with significant reduction of the LPS-induced immobility in both the forced swim and
tail suspension tests. These results demonstrated the antidepressant-like effects of amycenone in an
animal model of LPS-induced inflammation depression, suggesting its neuroprotective effects against
inflammation-associated depression. However, treatment of depression usually required long-term
administration of antidepressant and acute treatment might not provide a long-term therapeutic effect,
which might eventually trigger a recurrence. The experiments conducted by Yao et al. could be
improved by prolonging the study to examine the long-term antidepressant effects of amycenone.
The study by Ryu et al. in 2018 investigated the antidepressant and anxiolytic effects of H. erinaceus
ethanolic extract in adult mice [
32
]. They found that chronic administration of a high dose (60 mg/kg)
H. erinaceus extract significantly reduced the time spent in the peripheral region of the open field test,
suggesting a potential anxiolytic effect. Furthermore, immobility time was significantly reduced in
both the tail suspension test and forced swim test, indicating an anti-depressant-like effect. However,
the animal model in this study used naive animals that were not pre-exposed to stress. The effectiveness
of H. erinaceus as an antidepressant could vary between naive and depressed subjects, as they have
different behaviors and physiological responses. These results may be less convincing, as it is not
known if there are similar effects in depressed subjects. Chronic stress is a well-known method to induce
animal models of depression [
74
]. It has been shown that BDNF expression was significantly reduced
in the hippocampus of the chronic stressed-animals that exhibited depressive-like behaviors [
75
,
76
].
Hence, this animal model of depression could be an appropriate research model for studying the
antidepressant effects of H. erinaceus. It would also be interesting to examine if H. erinaceus extract can
restore BDNF levels and depressive behavior in chronic stressed-animals. The underlying mechanisms
of these effects would be worth investigating.
Int. J. Mol. Sci. 2020,21, 163 6 of 18
Table 1. The behavioral and physiological effects of different Hericium erinaceus extracts in the studies of depression.
Types of Study Authors Material Studied Method of
Extraction Dose and Dosage Research Model Behavioural Effects Physiological Effects/Mechanism
Pre-clinical
Yao et al., 2015 [33]
Amycenone®,
H. erinaceus
fruiting body extract
(0.5% hericenones and
6% amyloban)
Patented
extraction
50, 100, or 200 * mg/kg
amycenone (Amyloban®
3399), administered 60 min
prior to 0.5 mg/kg LPS
injection; P.O.
Male C57BL/6N mus
musculus (LPS-induced
inflammation model
of depression)
Anti-inflammatory and
antidepressant-like effects
•
Attenuate a rise in the serum TNF-
α
level induced
by LPS
•Increase the serum IL-10 level induced by LPS
Ryu et al., 2017 [32]H. erinaceus Ethanolic extract 10, 60 * mg/kg daily for
4 weeks; P.O.
Male C57BL/6mus musculus
Antidepressant-like and
anxiolytic effects
•Increase PCNA+, Ki67, BrdU+cells.
•Hippocampal neurogenesis.
Chiu et al., 2018 [31]Erinacine A enriched
H. erinaceus mycelium Ethanolic extract 100, 200 *, and 400 * mg/kg
daily for 4 weeks; P.O.
50 (10/group) male ICR mus
musculus (14 days restraint
stress induced model
of depression)
Antidepressant-like effects
•Induce BDNF/TrkB/PI3K/Akt/GSK-3βpathways.
•Inhibit NF-κB signalling
•Reduced IL-6 and TNF-αlevels
•Increase 5-HT, DA, NE levels
Clinical
Nagano et al., 2010 [77]H. erinaceus
fruiting body Water extract
500 * mg powdered fruiting
body of H. erinaceus
(Aso Biotech Inc) per cookie,
4 cookies daily for
4 weeks; P.O.
30 female participants Alleviate symptoms of
depression and anxiety
•N.A.
Inanaga, 2014 [78]
Amycenone®,
H. erinaceus
fruiting body extract
(0.5% hericenones
and 6% amyloban)
Patented
extraction
1950 mg/tablet (Amyloban
®
3399) 6 tablets, divided into
2 or 3 doses /day for
6 months; P.O.
1 male patient Improve neurocognitive
impairment
•N.A
Okamura et al., 2015 [
79
]
Amycenone®,
H. erinaceus
fruiting body extract
(0.5% hericenones
and 6% amyloban)
Patented
extraction
1950 mg/tablet (Amyloban
®
3399) 6 tablets, divided into
2 or 3 doses /day for
4 weeks; P.O.
8 female healthy
participants
Alleviate symptoms of
depression and anxiety
Alleviate sleep disorders
•Increase salivary levels of free-MHPG
Vigna et al., 2019 [80]
H. erinaceus
(80% mycelia and
20% fruiting body)
Water and
ethanolic extract
1200 * mg per capsules
(A.V.D. Reform s.r.l.),
3 capsules/day for
8 weeks; P.O.
62 females and 15 males
overweight or obese
participants
Alleviate symptoms of
depression and anxiety
Alleviate sleep disorders
•Increase circulating pro-BDNF level without any
significant change in BDNF circulating level
Indicator: * Dose of H. erinaceus with significant antidepressant-like effects.
Int. J. Mol. Sci. 2020,21, 163 7 of 18
A recent study by Chiu et al. (2018) investigated the effects of extracts of H. erinaceus enriched in
Erinacine A (
5
) in an animal model of depression induced by repeated restraint stress [
31
]. They found
that bioactive compounds extracted from the mycelium of H. erinaceus by ethanolic extraction
were enriched with erinacine A, which is believed to induce neurogenesis. They showed that the
extracts enriched with erinacine A reduced the immobility time in both the forced swim test and
tail suspension test, indicating it had antidepressant-like effects. However, they did not detect an
anxiolytic effect in the elevated plus-maze, which contradicted the previous findings by Ryu et al. in
2018 [
32
]. One possible reason for this discrepancy is that the two studies used different H. erinaceus
extracts, as
Chiu et al. (2018)
used the ethanolic extract enriched with erinacine A extracted from the
mycelium [
31
], whereas
Ryu et al. (2018)
used the ethanolic extract from the fruiting body [
32
]. Further
research on the anxiolytic effects of H. erinaceus is required to confirm these findings. The use of
extracts from H. erinaceus mycelium enriched with erinacine A may be advantageous, as erinacine A
was reported to enhance nerve growth factor (NGF) activity to promote neurite outgrowth and its
therapeutic effect was validated in the central nervous system of rats [
81
,
82
]. However, the use of these
extracts from H. erinaceus may not represent the anti-depressant effects of H. erinaceus in its natural state.
Furthermore, natural H. erinaceus contains many other erinacines, including erinacines A (
5
), B (
6
),
C (
7
), D (
8
), E (
9
), F (
10
), and H (
12
), which have been found to also enhance NGF synthesis [
81
,
83
–
85
].
Higher doses of natural H. erinaceus may provide a similar effect to the erinacine A-enriched extract
from H. erinaceus mycelium, and thus enrichment may not be necessary.
3.2. Clinical Studies
Prior to the
in vivo
studies that specifically looked at the antidepressant-like effects of H. erinaceus,
Nagano et al. (2010) studied the clinical effects of H. erinaceus on menopause, depression, sleep quality,
and indefinite complaints through a structured questionnaire survey of Kupperman Menopausal
Index, Center for Epidemiologic Studies Depression Scale, Pittsburgh Sleep Quality Index (PSQI),
and Indefinite Complaints Index in 30 females with an average age of 41.3 years over the period of
4 weeks [
77
]. Their findings revealed that consumption of cookies containing 0.5 g of fruitbodies powder
alleviated the symptoms of depression, anxiety, frustration, and palpitation. However, the conclusions
are less convincing as the study was gender-specific by design as it was related to menopause and also
because a small study population was used.
In 2014, Inanaga et al. reported an improvement in neurocognitive function after treatment
with Amyloban
®
3399 (tablets of standardized extract) in an 86-year-old male patient with recurrent
depressive disorder [
78
]. However, mirtazapine, an antidepressant drug was also administered
together with Amyloban
®
3399. Thus, the antidepressant effects could not be fully assessed in this
study whether the alleviation in mood was a result of mirtazapine or the Amyloban
®
3399 or both.
Additionally, a pilot study by Okamura et al. (2015) demonstrated that administration of Amyloban
®
3399 on female undergraduate students with sleep disorder for 4 weeks revealed an increase in the
salivary level of free 3-methoxy-4-hydroxyphenylglycol, a biological index of anxiety disorders, which
corresponds to an improvement in anxiety and sleep quality [
79
]. Sleep quality and general health
status were assessed by the General Health Questionnaire (GHQ-28) and PSQI. In this pilot study,
only eight female undergraduate students were recruited and who were scheduled to take a national
examination in about a month, the result is unconvincing as the studied population is small and
gender-specific. Furthermore, sleep disorder, anxiety, and mood disorder could be just temporary
effects associated with their preparation for the national examination, which is different from the
severity of clinically diagnosed anxiety and mood disorders.
Recently, a clinical study examined the effects of H. erinaceus on anxiety, depression, binge eating,
and sleep disorders in 77 volunteers with a body mass index (BMI)
≥
25 kg/m
2
and an average age of
53.2 [
80
]. The study recruited overweight or obese participants positive for one or more administered
tests, including Zung’s Depression Self-Assessment Scale, Zung’s Anxiety Self-Assessment Scale,
Symptom Checklist-90, and the binge eating scale (BES). Participants in the H. erinaceus intervention
Int. J. Mol. Sci. 2020,21, 163 8 of 18
group received three capsules containing 80% mycelium extract and 20% fruiting body extract daily
for 8 weeks. They found that H. erinaceus significantly reduced depression and anxiety, as well as
improvement on sleep disorders after 8 weeks of oral administration. The observation was linked
to an increase in peripheral pro-BDNF and in the pro-BDNF/BDNF ratio. However, it was not clear
whether these behavioral results might be partly due to a placebo effect from consuming a capsule.
The experimental design of this study could have been improved by including placebo capsules in the
control group and increasing the sample population. Although these studies showed that H. erinaceus
has anti-depressant effects in female patients with symptoms of menopause and in obese patients,
a clinical study on the antidepressant effects of H. erinaceus has yet to be conducted in the general
depression population with and without gender bias.
4. Bioactive Compounds of H. erinaceus that Contribute to Antidepressant-Like Activities
Fruiting bodies and mycelia of H. erinaceus contain a variety of structurally diverse bioactive compounds
that can induce the expression of various neurotrophic factors [
81
,
83
,
84
,
86
] and monoamines [
31
],
and modulate inflammatory response [
33
]. At present, most of the identified bioactive compounds that
contribute to antidepressant-like effects are mostly associated with NGF-inducing activity. The bioactive
compounds of H. erinaceus that affect NGF release can be narrowed down to hericenones and erinacines.
The small molecular sizes of hericenones and erinacines allow them to pass easily through the
blood–brain barrier. These two major bioactive compounds have been investigated in most of
the studies.
4.1. Hericenones
Hericenones are aromatic compounds extracted from the fruiting body of H. erinaceus. There
are 11 hericenones (hericenones A-K) that have been identified, of which four (hericenones C (
1
),
D (
2
), E (
3
), and H (
4
) (Figure 3)) have been reported to promote NGF synthesis in mouse astrocytoma
cells [
86
,
87
]. Mouse astroglial cells secreted 23.5
±
1.0, 10.8
±
0.8, 13.9
±
2.1, and 45.1
±
1.1 pg/mL NGF
after treatment with 33
µ
g/mL hericenones C, D, E, and H, respectively. However, Mori et al. (2008)
did not find that hericenones C, D, and E promoted NGF gene expressions at 10–100 mg/mL in 1321N1
human astrocytoma cells [
88
]. This raises the possibility that the NGF-promoting activity involves
other bioactive compounds besides hericenones. Further
in vivo
studies on hericenones are needed to
examine its effectiveness in stimulating NGF synthesis to resolve these inconsistent in vitro findings.
Int. J. Mol. Sci. 2020,21, 163 9 of 18
Int.J.Mol.Sci.2019,20,x
9of18
noradrenaline,anddopamine,aswellastheBDNFsignaling[31].However,thebioactive
compoundsthatcontributedtotheantidepressant‐likeeffectsremaintobeidentified.
Figure3.ChemicalstructuresofhericenoneC(1),D(2),E(3),H(4),erinacineA(5),H(12),B(6),C
(7),D(8),E(9),F(10),G(11),I(13),ergosterolperoxide(14),cerevisterol(15),and3β,5α‐trihydroxy‐
ergosta‐7,22‐dien‐6‐one(16).
5.MechanismofAction
5.1.StimulationofNGFandProliferativeActivities
Hippocampalneurogenesisisoneofthemajortherapeutictargetsforthetreatmentof
depressionbasedontheneurogenichypothesisofdepression.Bioactivecompoundsextractedfrom
H.erinaceusincludingitsmyceliaandfruitingbodieswerefoundtostimulatetheexpressionof
neurotrophicfactorssuchasNGF[81,84,86,87].IncreasedlevelsofNGFwerefoundtobeassociated
withneurogenesisandneuroplasticity[48],whichmaypotentiallyleadtoantidepressant‐likeeffects.
AstudybyRyuetal.(2018)foundthatchronicadministrationofH.erinaceusethanolicextract(60
mg/kg)significantlyincreasedthenumberofPCNA‐positivecellsandKi67‐positivecellsinthe
Figure 3.
Chemical structures of hericenone C (
1
), D (
2
), E (
3
), H (
4
), erinacine A (
5
), H (
12
), B (
6
),
C (
7
), D (
8
), E (
9
), F (
10
), G (
11
)
,
I (
13
), ergosterol peroxide (
14
), cerevisterol (
15
), and 3
β
,5
α
-trihydroxy-
ergosta-7,22-dien-6-one (16).
4.2. Erinacines
Erinacines have been mostly isolated from mycelium of H. erinaceus, however, erinacines A (
5
)
and B (
6
) can also be found in the fruiting bodies [
89
]. Erinacines belong to a group of cyathin
diterpenoids and have been shown to induce NGF synthesis. Currently, 15 erinacines have been
identified, including erinacines A–K, P, Q, and S [
81
,
82
,
84
,
85
,
90
–
92
]. Among these erinacines, erinacines
A-I (
5
–
13
) (Figure 3) were found to promote NGF synthesis, although other erinacines are still being
investigated [
81
,
82
,
84
,
85
,
90
,
93
]. However, the underlying mechanism of how erinacines enhance NGF
release remains unclear.
4.3. Novel Compounds
Many novel bioactive compounds of H. erinaceus are being actively discovered [
19
,
94
]. Other
than hericenones and erinacines, Zhang et al. (2015) found several newly identified compounds
Int. J. Mol. Sci. 2020,21, 163 10 of 18
isolated from the fruiting body of H. erinaceus, including ergosterol peroxide (
14
), cerevisterol (
15
),
and 3
β
,5
α
,9
α
-trihydroxy-ergosta-7,22-dien-6-one (
16
) (Figure 3), which exhibited NGF-inducing
activity and promoted neurite outgrowth in
in vitro
assays [
23
]. Additionally, amycenone isolated
from the fruiting body of H. erinaceus exhibited anti-inflammatory activity that alleviated the
inflammation-associated depression [
33
]. Of particular interest, the ethanolic extract of H. erinaceus
mycelium enriched with erinacine A was found to modulate the expression level of serotonin,
noradrenaline, and dopamine, as well as the BDNF signaling [
31
]. However, the bioactive compounds
that contributed to the antidepressant-like effects remain to be identified.
5. Mechanism of Action
5.1. Stimulation of NGF and Proliferative Activities
Hippocampal neurogenesis is one of the major therapeutic targets for the treatment of depression
based on the neurogenic hypothesis of depression. Bioactive compounds extracted from H. erinaceus
including its mycelia and fruiting bodies were found to stimulate the expression of neurotrophic factors
such as NGF [
81
,
84
,
86
,
87
]. Increased levels of NGF were found to be associated with neurogenesis and
neuroplasticity [
48
], which may potentially lead to antidepressant-like effects. A study by Ryu et al.
(2018) found that chronic administration of H. erinaceus ethanolic extract (60 mg/kg) significantly
increased the number of PCNA-positive cells and Ki67-positive cells in the subgranular zone of the
dentate gyrus, a region that consists of adult neural stem cells [
32
]. This result indicates that chronic
high-dose H. erinaceus could promote the proliferation of hippocampal neural stem or progenitor
cells. Furthermore, chronic administration of the H. erinaceus extract also increased the number
of bromodeoxyuridine (BrdU)-immunoreactive cells in the granule cell layer of the dentate gyrus.
Additionally, there was an increase in BrdU/NeuN double-labeled cell. These results indicate that
chronic high-dose H. erinaceus could increase the number of mature hippocampal neurons differentiated
from new neurons present prior to the first administration of H. erinaceus. Overall, these findings
showed that chronic high-dose H. erinaceus treatment could promote hippocampal neurogenesis and
increase the survival of new neurons in the dentate gyrus. The underlying mechanism of hippocampal
neurogenesis induced by H. erinaceus administration was suggested to involve NGF synthesis. Nerve
growth factor is necessary to regulate differentiation, proliferation, and maintenance of neuronal
cells. Extracts of H. erinaceus were found to increase both NGF mRNA and protein expression in
the hippocampus, indicating the bioactive compounds from H. erinaceus extract could pass through
the blood–brain barrier leading to hippocampal neurogenesis [
32
]. It was previously reported that
NGF levels were increased in the locus coeruleus and hippocampus of rats after receiving 8 mg/kg
erinacine A [
82
]. This is in line with the
in vitro
finding that ethanolic extract from the fruiting
body of H. erinaceus could promote neurite outgrowth in PC12 cells and stimulate NGF synthesis in
1321N1 human astrocytoma cells [
88
]. Mori et al. (2008) reported that H. erinaceus ethanolic extract
with 100
µ
g/mL significantly increased the NGF mRNA and protein expression in 1321N1 human
astrocytoma cells. They also found that 7 days of oral administration of 5% H. erinaceus dry powder
increased NGF gene expression in the hippocampus of mice [
88
]. In 2008, Mori et al. treated 1321N1
cells with several kinase inhibitors followed by H. erinaceus ethanolic extract. Hericium erinaceus
enhanced NGF activity, which was found to be inhibited by the c-Jun N-terminal kinase (JNK) inhibitor.
The JNK serine-threonine protein kinase is involved in the phosphorylation of its downstream substrate
c-Jun, a component of the activator protein 1 (AP-1) transcription factor [
88
]. Hericium erinaceus
ethanolic extract promoted the phosphorylation of JNK and c-Jun, as well as the expression of c-Fos
in vitro
. These results further suggest that H. erinaceus ethanolic extract enhances NGF synthesis
through the JNK pathway.
Int. J. Mol. Sci. 2020,21, 163 11 of 18
5.2. Monoaminergic Modulation
Modulation of monoamine neurotransmitters is another major therapeutic target for the treatment
of depression. Chiu et al. (2018) showed that 14 days of restraint stress reduced the levels of monoamines
neurotransmitters in the hippocampus of mice. Interestingly, the chronic administration of high-dose
(400 mg/kg) H. erinaceus mycelium extract effectively restored the depleted expression levels of
serotonin, norepinephrine, and dopamine in the hippocampus of restraint stressed-animals [
31
]. These
results suggest that H. erinaceus has anti-depressant-like effects through serotonergic, noradrenergic,
and dopaminergic modulations in restraint stressed animals. However, this finding raised the
question that how does H. erinaceus modulate the concentration of the monoamine neurotransmitters.
The detailed modulation pathway remains unknown and needed to be further investigated whether the
bioactive compound of H. erinaceus acts as an MAO inhibitor which inhibits the enzymatic degradation
of MAO thus preventing the reduction of monoamine neurotransmitters.
5.3. Anti-Inflammatory Pathway
To examine the anti-inflammatory effects of amycenone isolated from H. erinaceus fruiting body
extract, the LPS-induced inflammation model of depression was pre-treated with amycenone 1 h before
the intraperitoneal injection of LPS [
33
]. Blood was collected 90 min after the LPS injection for the
measurement of serum TNF-
α
and IL-10 levels. Acute oral administration of 50, 100, and 200 mg/kg
amycenone was found to attenuate the rise in serum TNF-
α
level induced by LPS, and 200 mg/kg
amycenone significantly increased the rise in serum IL-10 level induced by LPS injection. Both TNF-
α
and
IL-10 were previously reported to be associated with depression, in which TNF-
α
is a pro-inflammatory
cytokine, while IL-10 is an anti-inflammatory cytokine [
71
,
95
,
96
]. The attenuation of the rise in TNF-
α
level and the enhanced-upregulation of IL-10 by acute treatment of amycenone suggested that
the antidepressant-like effects of amycenone were through anti-inflammatory pathway. However,
the detailed molecular mechanisms of action are still needed to be investigated.
Additionally, chronic oral administration of 200 and 400 mg/kg H. erinaceus mycelium effectively
inhibited the increase in hippocampal expression levels of IL-6 and TNF-
α
induced by a paradigm
of chronic restraint stress in a mouse model [
31
]. This result suggests that the anti-depressant effect
of H. erinaceus involves the modulation of the inflammatory pathway. Related to an inflammatory
response, erinacine A isolated from H. erinaceus was also reported to have neuroprotective effects
against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity through oxidative
stress signaling and activation of the IRE1
α
/TRAF2, JNK1/2, and p38 MAPK pathways [
29
]. Although
an anti-inflammatory response was demonstrated after H. erinaceus treatment, the detailed underlying
molecular mechanisms remain unclear. Chiu et al. (2018) showed that chronic administration of
H. erinaceus was able to restore the expression levels of nuclear factor-kappa B (NF-
κ
B) and I
κ
B that
were reduced in the hippocampus of animals subjected to chronic restraint stress [
31
]. NF-
κ
B is an
important transcription factor in chronic inflammatory diseases, which is involved in the expression of
various proinflammatory genes such as chemokines, cytokines, and adhesion molecules [
97
]. Based
on these findings, the anti-depressant effects of H. erinaceus could be through an anti-inflammatory
response via modulating the expression levels of IL-6, TNF-α, and NF-κB.
5.4. BDNF Pathway
Other than the NGF pathway, H. erinaceus mycelium was also reported to activate BDNF/TrkB/
PI3K/Akt/GSK-3
β
pathways and inhibit NF-
κ
B signaling in mice [
31
]. Chronic administration of H. erinaceus
ethanolic extract was found to normalize the expression levels of BDNF, TrkB, and PI3K that were
downregulated in animals with chronic restraint stress [
31
]. In addition, chronic administration
of H. erinaceus inhibited the reduced expression levels of Akt-p and GSK-3
β
-p, but not Akt and
GSK-3
β
, in the hippocampus of mice induced by repeated restraint stress. Similarly, erinacine C (
1
)
isolated from H. erinaceus mycelium was reported to increase BDNF expression in 1321N1 cells [
98
].
Int. J. Mol. Sci. 2020,21, 163 12 of 18
The restoration effect of H. erinaceus on BDNF was suggested to be through monoaminergic modulation
and normalization, as BDNF can be influenced by monoaminergic transmitters such as serotonin,
norepinephrine, and dopamine [
99
]. A recent clinical study on patients with depression, anxiety,
and sleep disorder examined the beneficial effects of 8 weeks of oral administration of capsules
containing H. erinaceus extract (1200 mg/capsule, 3 capsules/day) [
80
]. They reported that pro-BDNF
levels in the blood serum increased after 4 weeks of H. erinaceus administration, but there were no
significant changes in serum BDNF levels. However, serum BDNF levels decreased after 8 weeks of
H. erinaceus administration. The detailed underlying mechanism of the role of BDNF expression in the
anti-depressant effects of H. erinaceus remains unclear.
Overall, these results suggest that H. erinaceus ameliorates depressive-like behavior through the
modulation of monoamine neurotransmitters and proinflammatory cytokines, as well as through the
activation of BDNF pathways (Figure 4).
Int.J.Mol.Sci.2019,20,x
12of18
Figure4.Summaryofthegenerationofdepressive‐likebehaviorsinducedbychronicstressandLPS‐
inducedinflammation,aswellasthemechanismsofantidepressant‐likeeffectsinducedbyH.
erinaceus.Theuparrowindicatesanincreaseintheactivity/expressionlevel,whilethedownarrow
indicatesadecreaseintheactivity/expressionlevel.
6.FuturePerspectivesofH.erinaceusResearchinDepressiveDisorder
Hericiumerinaceuscrudeextractcontainsvarioushericenones,erinacines,andpossiblyother
bioactivecompoundsthatarestillbeingdiscovered.Overall,thepotentNGF‐enhancingactivitiesof
H.erinacinesarepossiblymediatedthroughthesynergisticeffectsofseveralcompoundsinthecrude
extract.Thesecompoundscangreatlyenhanceadulthippocampalneurogenesisandcontributeto
theantidepressant‐likeeffects.Chronicstressisknowntoinduceananhedoniaeffectthatishighly
associatedwithdepression[100,101].However,theanti‐anhedoniaactivityofH.erinaceushasnot
beenreportedyetandneedstobeinvestigatedinfuturestudies.Furthermore,itwouldbeinteresting
toexamineifhericenones,erinacines,or/andothercompoundsofH.erinaceuscanbeabsorbedinthe
bloodandpassthroughtheblood–brainbarrier.Thevarietyofbioactivecompoundswithpotent
NGF‐inducingactivityalsosupportstheuseofcrudeextractratherthanpureextracts.Themajority
ofstudiesonH.erinaceusbioactivecompoundshavefocusedontheirNGFactivities.Futurestudies
ontheantidepressantactivityofthesebioactivecompoundsneedtoexaminetheireffectsonthe
expressionofBDNF.AlthoughBDNFwasfoundtoberestoredinthehippocampusafterchronic
administrationofH.erinaceus,itisstillunclearwhethertheincreaseisalsoreflectedinperipheral
BDNFexpressions[80].TheinvestigationoftheeffectsonperipheralBDNFexpressionmayprovide
Figure 4.
Summary of the generation of depressive-like behaviors induced by chronic stress and
LPS-induced inflammation, as well as the mechanisms of antidepressant-like effects induced by
H. erinaceus. The up arrow indicates an increase in the activity/expression level, while the down arrow
indicates a decrease in the activity/expression level.
6. Future Perspectives of H. erinaceus Research in Depressive Disorder
Hericium erinaceus crude extract contains various hericenones, erinacines, and possibly other
bioactive compounds that are still being discovered. Overall, the potent NGF-enhancing activities
Int. J. Mol. Sci. 2020,21, 163 13 of 18
of H. erinacines are possibly mediated through the synergistic effects of several compounds in the
crude extract. These compounds can greatly enhance adult hippocampal neurogenesis and contribute
to the antidepressant-like effects. Chronic stress is known to induce an anhedonia effect that is
highly associated with depression [
100
,
101
]. However, the anti-anhedonia activity of H. erinaceus
has not been reported yet and needs to be investigated in future studies. Furthermore, it would
be interesting to examine if hericenones, erinacines, or/and other compounds of H. erinaceus can be
absorbed in the blood and pass through the blood–brain barrier. The variety of bioactive compounds
with potent NGF-inducing activity also supports the use of crude extract rather than pure extracts.
The majority of studies on H. erinaceus bioactive compounds have focused on their NGF activities.
Future studies on the antidepressant activity of these bioactive compounds need to examine their
effects on the expression of BDNF. Although BDNF was found to be restored in the hippocampus
after chronic administration of H. erinaceus, it is still unclear whether the increase is also reflected in
peripheral BDNF expressions [
80
]. The investigation of the effects on peripheral BDNF expression
may provide important information for future clinical studies of depression. Moreover, as chronic
administration of H. erinaceus was found to increase peripheral pro-BDNF but not BDNF [
80
], it would
be interesting to examine the association of neurotrophic isoforms with depressive-like behaviors
and whether H. erinaceus also affects their expression. In addition, as H. erinaceus was shown to
stimulate monoaminergic modulation, it would be interesting to examine if the bioactive compounds of
H. erinaceus act as agonists or inhibitors of monoamine neurotransmitter receptors. Although treatment
with H. erinaceus was found to elicit an anti-inflammatory response, the detailed molecular mechanism
is still unknown. These studies provide evidence that H. erinaceus possesses potential in alleviating
depression, but the precise underlying mechanisms remain to be investigated. However, there is still a
lack of strong and convincing evidence that H. erinaceus can effectively reduce anxiety and depression
in vivo
, which requires further investigation. Moreover, compounds in the extracts from the mycelium
and fruiting body, as well as the method of extraction, requires further investigation to optimize the
efficacy of H. erinaceus as a treatment for depressive disorders. In present investigation, majority of
the studies does not include placebo or positive controls; and therefore, conventional antidepressants
should be included as a positive control in future placebo-controlled research to compare their efficacy
and eliminate potential placebo or non-specific effect. Furthermore, there is no concrete evidence of
bioactive compounds unique to H. erinaceus that are responsible for its therapeutic effects, therefore
future investigations involving selected medicinal-culinary mushrooms are highly warranted to rule
out placebo and/or general effects.
7. Conclusions
The pre-clinical and clinical studies have demonstrated that H. erinaceus significantly
ameliorates depressive disorder through monoaminergic modulation, neurogenic/neurotrophic,
and anti-inflammatory pathways, indicating the potential role of H. erinaceus as complementary
and alternative medicine for the treatment of depression. Nevertheless, the current research on
antidepressant effects by H. erinaceus is relatively still at an early stage, and the specific mechanisms
underlying the antidepressant-like activities require further investigation.
Author Contributions:
Conceptualization, L.W.L., K.H.W. and P.S.C.; Writing—Original draft preparation, P.S.C.;
Writing—Review and editing, L.W.L., K.H.W., M.-L.F. and P.S.C.; Visualization, P.S.C.; Supervision, M.-L.F., L.W.L.
and K.H.W. All authors have read and agreed to the published version of the manuscript.
Funding:
The scientific work was funded by grants from the Hong Kong Research Grant Council, and the
University of Hong Kong Seed Fund for Translational and Applied Research (201811160028) awarded to L.W.L.
Conflicts of Interest: All authors declare no conflict of interest.
Int. J. Mol. Sci. 2020,21, 163 14 of 18
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