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Therapeutic Potential of Hericium erinaceus for Depressive Disorder


Abstract and Figures

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. Based on the neurotrophic and neurogenic pathophysiology of depression, Hericium erinaceus may be a potential alternative medicine for the treatment of depression with fewer side effects. This article critically reviews the current literature on the potential benefits of H. erinaceus as a treatment for mood and anxiety disorders as well as the underlying mechanisms.
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International Journal of
Molecular Sciences
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; (P.S.C.); (M.-L.F.)
2Department of Anatomy, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia
*Correspondence: (K.H.W.); (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
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
ecacies are barely adequate and many have side eects. 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 eects. 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 eects 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.
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
aects more than 300 million people of all ages [
] and is one of the leading causes of global disease
burden [
]. The common signs and symptoms of depression include loss of interest in daily activities,
diculty concentrating and making decisions, fatigue, sleep problems, overeating or appetite loss,
pessimism, hopelessness, persistent sadness, and restlessness [
]. Untreated depression could lead
to suicidal thoughts or suicide attempts [
]. 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 [
]. 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 [
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 ecacy is still barely satisfactory [
]. Studies of
Int. J. Mol. Sci. 2020,21, 163; doi:10.3390/ijms21010163
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 [
]. Furthermore,
antidepressant medication often needs to be administered continuously for years to prevent relapse [
Besides, more than 50% of antidepressant users reported that they experienced side eects, 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 [
]. The side eects can often lead to failure in the
administration of antidepressants in depressive patients [12,13].
Herbal medicine can be a cost-eective complementary and alternative medicine for the treatment
of depressive disorders, generally with fewer side eects and limited comparative ecacy to
conventional antidepressants, as well as it is well-tolerated by depressive patients [
]. Mushrooms
are functional foods with high nutritional values and are great sources for novel therapeutic
compounds [
]. 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 [
]. Hericium erinaceus has a long history as a medicine [
] 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 [
]. Bioactive
compounds extracted from its fruiting body or mycelium (Figure 1) have been demonstrated to possess
antioxidative [
], antidiabetic [
], anticancer [
], anti-inflammatory [
], antimicrobial [
antihyperglycemic [
], and hypolipidemic properties [
]. Moreover, H. erinaceus has been used
to treat cognitive impairments [
], Alzheimer’s disease [
], Parkinson’s disease [
], ischemic
stroke [
], and presbycusis [
]. Recently, the present research on H. erinaceus has been focused on
its antidepressant-like eects for the treatment of depressive disorder [
]. Up to date, no review
concerning the antidepressant eects of H. erinaceus is available. The aim of this review is to critically
review the current literature on the potential antidepressant eects of H. erinaceus as a treatment for
depressive disorder as well as its possible mechanisms underlying the antidepressant-like responses.
Figure1. FruitingbodiescultivatedatthetropicalclimateinMalaysia(A,B)andmycelia(C)of
Figure 1.
Fruiting bodies cultivated at the tropical climate in Malaysia (
) and mycelia (
) 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 [
]. 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 [
]. 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 [
]. 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 [
]. Interestingly,
in vivo
found that animals treated with reserpine exhibited depressive-like behavior, which is in line with
clinical findings [
]. 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 [
]. Iproniazid and other monoamine oxidase inhibitors
were subsequently found to be eective in improving symptoms of depression, which strongly supports
the monoamine hypothesis of depression. Similarly, antidepressant-like eects 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].
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 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 [
]. 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 [4346]. 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 [
]. Brain-derived neurotrophic factor (BDNF) is one of the neurotrophic factors that are highly
associated with suicidal and depressive behaviors [
]. Although animal studies showed a decrease
in BDNF level was not sucient 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 [
]. Anti-depressant treatments that restored or increased BDNF levels
were able to alleviate symptoms of depression [
]. 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 [
]. BDNF functions by binding to its receptors, including tropomyosin receptor kinase
B (TrkB) and pan 75 neurotrophin receptor (p75
), a low-anity receptor. The binding anity
of p75
towards BDNF was found to be increased with less Trk receptors or Trk inactivity [
This interaction can induce neuronal apoptosis in oligodendrocytes, vascular smooth muscle cells,
and neuronal cells [
]. 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
) and interleukin-1,
interleukin-6 (IL-1, IL-6), and interferon-
]. 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 [
]. Furthermore, animal models of inflammation-associated depression are often generated
through the administration of cytokines or cytokine inducers, including IL-6 and lipopolysaccharide
(LPS) [
]. 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 [
]. An
in vivo
study also showed that stress stimulus significantly increases
the level of proinflammatory cytokines including TNF-
and IL-18 in the prefrontal cortex and
hippocampus [
]. 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
]. Patients with the first episode of depression and those who experiencing recurrent depressive
disorders were reported to have no dierence 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 [
Additionally, TNF-
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 [
]. 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 [
]. In 2015, Yao et al. reported the
antidepressant-like and anti-inflammatory eects of amycenone in an animal model of depression
with LPS-induced inflammation [
]. 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 eects of amycenone in an
animal model of LPS-induced inflammation depression, suggesting its neuroprotective eects 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 eect,
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 eects of amycenone.
The study by Ryu et al. in 2018 investigated the antidepressant and anxiolytic eects of H. erinaceus
ethanolic extract in adult mice [
]. 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 eect. Furthermore, immobility time was significantly reduced in
both the tail suspension test and forced swim test, indicating an anti-depressant-like eect. However,
the animal model in this study used naive animals that were not pre-exposed to stress. The eectiveness
of H. erinaceus as an antidepressant could vary between naive and depressed subjects, as they have
dierent behaviors and physiological responses. These results may be less convincing, as it is not
known if there are similar eects in depressed subjects. Chronic stress is a well-known method to induce
animal models of depression [
]. It has been shown that BDNF expression was significantly reduced
in the hippocampus of the chronic stressed-animals that exhibited depressive-like behaviors [
Hence, this animal model of depression could be an appropriate research model for studying the
antidepressant eects 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 eects would be worth investigating.
Int. J. Mol. Sci. 2020,21, 163 6 of 18
Table 1. The behavioral and physiological eects of dierent Hericium erinaceus extracts in the studies of depression.
Types of Study Authors Material Studied Method of
Extraction Dose and Dosage Research Model Behavioural Eects Physiological Eects/Mechanism
Yao et al., 2015 [33]
H. erinaceus
fruiting body extract
(0.5% hericenones and
6% amyloban)
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 eects
Attenuate a rise in the serum TNF-
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 eects
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 eects
Induce BDNF/TrkB/PI3K/Akt/GSK-3βpathways.
Inhibit NF-κB signalling
Reduced IL-6 and TNF-αlevels
Increase 5-HT, DA, NE levels
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
Inanaga, 2014 [78]
H. erinaceus
fruiting body extract
(0.5% hericenones
and 6% amyloban)
1950 mg/tablet (Amyloban
3399) 6 tablets, divided into
2 or 3 doses /day for
6 months; P.O.
1 male patient Improve neurocognitive
Okamura et al., 2015 [
H. erinaceus
fruiting body extract
(0.5% hericenones
and 6% amyloban)
1950 mg/tablet (Amyloban
3399) 6 tablets, divided into
2 or 3 doses /day for
4 weeks; P.O.
8 female healthy
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
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 eects.
Int. J. Mol. Sci. 2020,21, 163 7 of 18
A recent study by Chiu et al. (2018) investigated the eects of extracts of H. erinaceus enriched in
Erinacine A (
) in an animal model of depression induced by repeated restraint stress [
]. 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 eects. However, they did not detect an
anxiolytic eect in the elevated plus-maze, which contradicted the previous findings by Ryu et al. in
2018 [
]. One possible reason for this discrepancy is that the two studies used dierent H. erinaceus
extracts, as
Chiu et al. (2018)
used the ethanolic extract enriched with erinacine A extracted from the
mycelium [
], whereas
Ryu et al. (2018)
used the ethanolic extract from the fruiting body [
]. Further
research on the anxiolytic eects 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 eect was validated in the central nervous system of rats [
]. However, the use of these
extracts from H. erinaceus may not represent the anti-depressant eects of H. erinaceus in its natural state.
Furthermore, natural H. erinaceus contains many other erinacines, including erinacines A (
), B (
C (
), D (
), E (
), F (
), and H (
), which have been found to also enhance NGF synthesis [
Higher doses of natural H. erinaceus may provide a similar eect 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 eects of H. erinaceus,
Nagano et al. (2010) studied the clinical eects 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 [
]. 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 [
]. However, mirtazapine, an antidepressant drug was also administered
together with Amyloban
3399. Thus, the antidepressant eects 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 [
]. 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
eects associated with their preparation for the national examination, which is dierent from the
severity of clinically diagnosed anxiety and mood disorders.
Recently, a clinical study examined the eects of H. erinaceus on anxiety, depression, binge eating,
and sleep disorders in 77 volunteers with a body mass index (BMI)
25 kg/m
and an average age of
53.2 [
]. 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 eect 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 eects in female patients with symptoms of menopause and in obese patients,
a clinical study on the antidepressant eects 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 [
] and monoamines [
and modulate inflammatory response [
]. At present, most of the identified bioactive compounds that
contribute to antidepressant-like eects are mostly associated with NGF-inducing activity. The bioactive
compounds of H. erinaceus that aect 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 (
D (
), E (
), and H (
) (Figure 3)) have been reported to promote NGF synthesis in mouse astrocytoma
cells [
]. 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
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 [
]. 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 eectiveness in stimulating NGF synthesis to resolve these inconsistent in vitro findings.
Int. J. Mol. Sci. 2020,21, 163 9 of 18
Figure 3.
Chemical structures of hericenone C (
), D (
), E (
), H (
), erinacine A (
), H (
), B (
C (
), D (
), E (
), F (
), G (
I (
), ergosterol peroxide (
), cerevisterol (
), and 3
ergosta-7,22-dien-6-one (16).
4.2. Erinacines
Erinacines have been mostly isolated from mycelium of H. erinaceus, however, erinacines A (
and B (
) can also be found in the fruiting bodies [
]. 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 [
]. Among these erinacines, erinacines
A-I (
) (Figure 3) were found to promote NGF synthesis, although other erinacines are still being
investigated [
]. 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 [
]. 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 (
), cerevisterol (
and 3
-trihydroxy-ergosta-7,22-dien-6-one (
) (Figure 3), which exhibited NGF-inducing
activity and promoted neurite outgrowth in
in vitro
assays [
]. Additionally, amycenone isolated
from the fruiting body of H. erinaceus exhibited anti-inflammatory activity that alleviated the
inflammation-associated depression [
]. 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 [
]. However, the bioactive compounds
that contributed to the antidepressant-like eects 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 [
]. Increased levels of NGF were found to be associated with neurogenesis and
neuroplasticity [
], which may potentially lead to antidepressant-like eects. 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 [
]. 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 dierentiated
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 dierentiation, 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 [
]. It was previously reported that
NGF levels were increased in the locus coeruleus and hippocampus of rats after receiving 8 mg/kg
erinacine A [
]. 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 [
]. Mori et al. (2008) reported that H. erinaceus ethanolic extract
with 100
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 [
]. 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 [
]. 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 eectively restored the depleted expression levels of
serotonin, norepinephrine, and dopamine in the hippocampus of restraint stressed-animals [
]. These
results suggest that H. erinaceus has anti-depressant-like eects 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 eects 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 [
]. Blood was collected 90 min after the LPS injection for the
measurement of serum TNF-
and IL-10 levels. Acute oral administration of 50, 100, and 200 mg/kg
amycenone was found to attenuate the rise in serum TNF-
level induced by LPS, and 200 mg/kg
amycenone significantly increased the rise in serum IL-10 level induced by LPS injection. Both TNF-
IL-10 were previously reported to be associated with depression, in which TNF-
is a pro-inflammatory
cytokine, while IL-10 is an anti-inflammatory cytokine [
]. The attenuation of the rise in TNF-
level and the enhanced-upregulation of IL-10 by acute treatment of amycenone suggested that
the antidepressant-like eects 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 eectively
inhibited the increase in hippocampal expression levels of IL-6 and TNF-
induced by a paradigm
of chronic restraint stress in a mouse model [
]. This result suggests that the anti-depressant eect
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 eects
against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity through oxidative
stress signaling and activation of the IRE1
/TRAF2, JNK1/2, and p38 MAPK pathways [
]. 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-
B) and I
B that
were reduced in the hippocampus of animals subjected to chronic restraint stress [
]. NF-
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 [
]. Based
on these findings, the anti-depressant eects 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/
pathways and inhibit NF-
B signaling in mice [
]. 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 [
]. In addition, chronic administration
of H. erinaceus inhibited the reduced expression levels of Akt-p and GSK-3
-p, but not Akt and
, in the hippocampus of mice induced by repeated restraint stress. Similarly, erinacine C (
isolated from H. erinaceus mycelium was reported to increase BDNF expression in 1321N1 cells [
Int. J. Mol. Sci. 2020,21, 163 12 of 18
The restoration eect 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 [
]. A recent clinical study on patients with depression, anxiety,
and sleep disorder examined the beneficial eects of 8 weeks of oral administration of capsules
containing H. erinaceus extract (1200 mg/capsule, 3 capsules/day) [
]. 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 eects 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).
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 eects 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 eects of several compounds in the
crude extract. These compounds can greatly enhance adult hippocampal neurogenesis and contribute
to the antidepressant-like eects. Chronic stress is known to induce an anhedonia eect that is
highly associated with depression [
]. 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
eects 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 [
]. The investigation of the eects 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 [
], it would
be interesting to examine the association of neurotrophic isoforms with depressive-like behaviors
and whether H. erinaceus also aects 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 eectively 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
ecacy 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 ecacy
and eliminate potential placebo or non-specific eect. Furthermore, there is no concrete evidence of
bioactive compounds unique to H. erinaceus that are responsible for its therapeutic eects, therefore
future investigations involving selected medicinal-culinary mushrooms are highly warranted to rule
out placebo and/or general eects.
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 eects 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.
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.
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... Granted it must be recognized that this potential stress-alleviating effect was only observed on completion of the Stress Visual Analogue Scales and no difference was observed for treatment groups for responses to the Perceived Stress Scale. As detailed in a recent review, there are several mechanisms of action that might underpin the mood effects of H. erinaceus [37], namely that several bioactive compounds of H. erinaceus can stimulate the expression of neurotrophic factors including nerve growth factor [11,[38][39][40]. Interestingly, serum nerve growth factor levels have previously been observed to be significantly reduced in individuals with major depressive disorder, compared to control samples [41,42]. ...
... However, the modulation pathway here remains unknown and further investigation is required to determine how H. erinaceus could modulate monoamine neurotransmitters. Additionally, the anti-inflammatory effects of H. erinaceus may exert mood enhancing effects by modulation of the expression of IL-6, TNF-α and NF-κB [37,43]. Finally, given that BDNF at both basic mechanism level, and variants, is suggested as an arbitrator of vulnerability to stress and stress-related disorders [44], the ability of H. erinaceus to interact with BDNF pathways may offer a mechanistic explanation for mood-enhancing effects. ...
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Background: Given the bioactive properties and limited work to date, Hericium erinaceus (Lion’s mane) shows promise in improving cognitive function and mood. However, much of the human research has concentrated on chronic supplementation in cognitively compromised cohorts. Objective: The current pilot study investigated the acute and chronic (28-day) cognitive and mood-enhancing effects of Hericium erinaceus in a healthy, young adult cohort. Design: This randomized, double-blind, placebo-controlled, parallel-groups design investigated the acute (60 min post dose) and chronic (28-day intervention) effects of 1.8 g Hericium erinaceus in 41 healthy adults aged 18–45 years. Results: Analysis revealed that following a single dose of Hericium erinaceus, participants performed quicker on the Stroop task (p = 0.005) at 60 min post dose. A trend towards reduced subjective stress was observed following 28-day supplementation (p = 0.051). Conclusions: The findings tentatively suggest that Hericium erinaceus may improve speed of performance and reduce subjective stress in healthy, young adults. However, null and limited negative findings were also observed. Given the small sample size, these findings should be interpreted with caution. Further investigation in larger sample sizes is crucial, however the findings of this trial offer a promising avenue of interest.
... Positive effects of H. erinaceus have been observed in the treatment of cognitive disorders, Alzheimer's disease, ischemic strokes, Parkinson's disease, and age-related hearing impairment [15,[21][22][23][24]. Promising results have also been obtained in the treatment of depressive disorders [25][26][27][28][29]. The studies referred to above were conducted on animal models ( Figure 1). ...
... Mori et al. [34] also conducted a study to investigate the impact of oral administration of H. erinaceus fruiting body powder for 23 days in mice with cognitive and learning deficits induced by Aβ (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) peptide administration. Researchers assessed learning function and demonstrated that H. erinaceus supplementation improved cognitive deficits induced by the amyloid peptide. ...
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Hericium erinaceus is a valuable mushroom known for its strong bioactive properties. It shows promising potential as an excellent neuroprotective agent, capable of stimulating nerve growth factor release, regulating inflammatory processes, reducing oxidative stress, and safeguarding nerve cells from apoptosis. The active compounds in the mushroom, such as erinacines and hericenones, have been the subject of research, providing evidence of their neuroprotective effects. Further research and standardization processes for dietary supplements focused on H. erinaceus are essential to ensuring effectiveness and safety in protecting the nervous system. Advancements in isolation and characterization techniques, along with improved access to pure analytical standards, will play a critical role in achieving standardized, high-quality dietary supplements based on H. erinaceus. The aim of this study is to analyze the protective and nourishing effects of H. erinaceus on the nervous system and present the most up-to-date research findings related to this topic.
... It is noteworthy that 10-50 µg/mL of LAH significantly promoted cell proliferative activity. Studies have shown that bioactive compounds in natural products have a promoting effect on the expression of growth factors associated with cell proliferation, e.g., the ethanol extract of Hericium erinaceus enhanced the synthesis of neurotrophic factor (NGF) through the JNK pathway, which promoted the proliferation of hippocampal neural stem cells [60]. It is hypothesized that the promoting effect of LAH on cell proliferation may be related to its promotion of growth factor expression. ...
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Inflammation is the host response of immune cells during infection and traumatic tissue injury. An uncontrolled inflammatory response leads to inflammatory cascade, which in turn triggers a variety of diseases threatening human and animal health. The use of existing inflammatory therapeutic drugs is constrained by their high cost and susceptibility to systemic side effects, and therefore new therapeutic candidates for inflammatory diseases need to be urgently developed. Natural products are characterized by wide sources and rich pharmacological activities, which are valuable resources for the development of new drugs. This study aimed to uncover the alleviating effect and potential mechanism of natural product Limonium aureum (LAH) on LPS-induced inflammatory responses in macrophages. The experimental results showed that the optimized conditions for LAH ultrasound-assisted extraction via response surface methodology were an ethanol concentration of 72%, a material-to-solvent ratio of 1:37 g/mL, an extraction temperature of 73 °C, and an extraction power of 70 W, and the average extraction rate of LAH total flavonoids was 0.3776%. Then, data of 1666 components in LAH ethanol extracts were obtained through quasi-targeted metabolomics analysis. The ELISA showed that LAH significantly inhibited the production of pro-inflammatory cytokines while promoting the secretion of anti-inflammatory cytokines. Finally, combined with the results of network pharmacology analysis and protein expression validation of hub genes, it was speculated that LAH may alleviate LPS-induced inflammatory responses of macrophages through the AKT1/RELA/PTGS2 signaling pathway and the MAPK3/JUN signaling pathway. This study preliminarily revealed the anti-inflammatory activity of LAH and the molecular mechanism of its anti-inflammatory action, and provided a theoretical basis for the development of LAH as a new natural anti-inflammatory drug.
... Moreover, it inhibits monoamine oxidase (MAO), resulting in the upregulation of crucial monoaminergic neurotransmitters like serotonin, norepinephrine, and dopamine. Through the reduction of pro-inflammatory factors like IL-6, TNF-α, and NF-κB, coupled with the elevation of BDNF levels, Hericium erinaceus exhibits antidepressant effects [83]. This mushroom also showcases anti-oxidative and anti-inflammatory properties, rendering it suitable for addressing cognitive impairment [84]. ...
Depression is a global mental health challenge with significant social and economic burdens. While conventional pharmacological treatments have been the cornerstone in depression management, there is a growing interest in exploring alternative and complementary herbal therapies. Herbal interventions have emerged as promising therapeutic approaches for depression treatment. Both clinical and preclinical research has shown that individuals with depression often experience simultaneous activation of neuro-inflammatory response within immune system and heightened activity in hypothalamus pituitary-adrenal (HPA) axis of neuroendocrine system. These two systems interact with each other bidirectionally through neural, immunological and humoral mechanisms. This review article provides an outline of the current progress of research on herbal interventions, emphasizing their potential as emerging therapeutics for depression. It discusses the mechanisms of action, safety profiles, and evidence from clinical studies supporting the use of various herbal remedies. Herbal interventions and traditional Chinese formulations hold promise as a valuable adjunct or alternative to conventional treatments, offering new avenues for the comprehensive care of individuals with depression.
... Some previous studies reported on the mushrooms' potential as a dietary supplement (or nutraceuticals) (Nallathamby et al., 2018;Wong, 2018;Chong et al., 2019); the knowledge and practices of wild edible mushrooms in Sabah (Foo et al., 2018); and the level of knowledge and consumers' perception toward mushroom -based products in Malaysia (Amin et al., 2017). However, studies on the level of knowledge, attitudes, and practices (KAP) about mushrooms as food and food supplements is still scarce in Malaysia. ...
Cultivation and consumption of the superfood, mushrooms are recommended due to their high nutritive value, medicinal properties and ease of cultivation. This study was designed to investigate the knowledge, attitudes and practices toward mushrooms as food and food supplements among Klang Valley residents. Data were collected using a structured questionnaire from a total of 385 respondents. Results revealed that a significant association (p<0.05) was found between level of knowledge and practices towards mushrooms as food and food supplements. Price, taste, and health benefits were the top three factors affecting participants’ preference when choosing mushrooms, processed mushroom food products and mushroom supplements. Moreover, age and monthly income showed a significant association (p<0.05) with level of knowledge, attitudes, and practices towards mushrooms as food and food supplements while ethnicity was significantly associated (p<0.05) with both level of attitudes and practices only. In conclusion, Klang Valley residents exhibited a high level of knowledge towards fresh mushrooms and processed mushroom food products, however, the appreciation and utilisation of mushrooms were still lacking as both level of attitude and level of practices were at moderate level. Corrective measures such as increasing public education on mushrooms are hence of top priority.
... Ganoderma lingzhi (Reishi Mushrooms) Ganoderma lucidum 0.02-0.98 (Ganoderma spp.) [60] Clinical Trial Fatigue in hormone therapy cancer patients [61] Mushroom extracts in trademarket, traditional Chinese medicine for insomnias, In animals, sleep disorder [62], anti-insomnia, In silico [63] Hericium erinaceus (Lion's Mane Mushroom) 1 [64] Depressive disorder Reviews [65,66] Clinical Trial Alzheimer's disease (NCT04065061) [67] Mushroom extracts in trademarket Clinical Trials_Sleep Disorders [68,69] Lactarius deliciosus 1.29 [48] in vitro-antioxidant and anti-hyperglycemic [70]. Depression [66] Not found Armillaria mellea 22.9 [48] In animals, memory [71] Mushroom extract in trademarket Traditional Chinese medicine for insomnias in animals, sleep disorder [72] Μushrooms constitute a special source of melatonin and related indole compounds [48,51,52]. ...
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Circadian rhythm consists of complicated molecular mechanisms to orchestrate environmental stimuli to intrinsic molecular clocks. However, circadian rhythm is frequently deregulated in modern society by both extrinsic and biological factors leading to Circadian Rhythm Sleep Disorders (CRSD).
... By promoting the growth and protection of neurons, hericenones may help to support brain health and potentially slow down the progression of neurodegenerative diseases such as Alzheimer's [124]. Erinacines, on the other hand, are a group of compounds that stimulate the production of nerve growth factors and promote the formation of new neurons [125]. A clump of lion's mane mushrooms is shown in Figure 7. ...
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Mushrooms are new potential sources of valuable medicines, long neglected because of difficulties experienced in their cultivation. There is a large variety of medicinal mushrooms which possess significant therapeutic properties and are used as medications for various diseases because they contain several novel highly bioactive components. Medicinal mushrooms can be identified based on their morphology, size, mass, and the color of the stalk, cap and spore, and attachment to the stalk. Medicinal mushrooms possess a variety of important biological activities and are used as antioxidants, hepatoprotectors, anticancer, antidiabetic, anti-inflammatory, antiaging, antiviral, antiparasitic, and antimicrobial agents, among others. This review provides a basic overview of the chemical scaffolds present in mushrooms and their therapeutic implications in the human body.
... Furthermore, synthetic medications may sometimes lead to maladaptive responses, and individuals with treatment-resistant depression face a higher risk of relapse [7]. On the other hand, natural functional materials tend to be cost-effective, with fewer side effects compared to traditional antidepressants, and they are well-received by individuals struggling with depression due to their high adaptability [8]. Therefore, there is ...
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Sargassum horneri, a brown seaweed, is known for its various health benefits; however, there are no reports on its effects on depression. This study aimed to investigate the antidepressant effects of S. horneri ethanol extract (SHE) in mice injected with corticosterone (CORT) and to elucidate the underlying molecular mechanisms. Behavioral tests were conducted, and corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and CORT levels were measured. A fluorometric monoamine oxidase (MAO) enzyme inhibition assay was performed. Neurotransmitters like serotonin, dopamine, and norepinephrine levels were determined. Moreover, the ERK-CREB-BDNF signaling pathway in the prefrontal cortex and hippocampus was evaluated. Behavioral tests revealed that SHE has antidepressant effects by reducing immobility time and increasing time spent in open arms. Serum CRH, ACTH, and CORT levels decreased in the mice treated with SHE, as did the glucocorticoid-receptor expression in their brain tissues. SHE inhibited MAO-A and MAO-B activities. In addition, SHE increased levels of neurotransmitters. Furthermore, SHE activated the ERK-CREB-BDNF pathway in the prefrontal cortex and hippocampus. These findings suggest that SHE has antidepressant effects in CORT-injected mice, via the regulation of the hypothalamic-pituitary-adrenal axis and monoaminergic pathway, and through activation of the ERK-CREB-BDNF signaling pathway. Thus, our study suggests that SHE may act as a natural antidepressant.
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This article delves into the profound significance of the early diagnosis of Alzheimer’s disease (AD), the leading cause of dementia worldwide. With no current cure for AD, early detection stands as a cornerstone in managing the disease. Early diagnosis not only enables symptomatic treatment to enhance the quality of life but also facilitates proactive planning, addressing health care and living arrangements for the future. Additionally, early diagnosis can promote participation in clinical trials, granting patients access to emerging treatments. An essential component to this early detection is a robust understanding of the disease's causes. The paper examines the pathological indicators, such as beta-amyloid plaques and neurofibrillary tangles, while highlighting the multifaceted origins of AD encompassing genetics, environmental factors, inflammation, and potential links with other diseases. An in-depth discussion on the influence of the environment further illustrates the complex interplay between genetics and external factors. Toxic chemicals, lifestyle choices in western societies, and other environmental determinants are scrutinized for their potential role in AD onset. In summary, the piece underscores the importance of a holistic understanding of Alzheimer's etiology, emphasizing that only through comprehensive knowledge can we aspire to identify, manage, and ultimately find a cure for this debilitating condition.
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Epidemiological data indicate that subjects affected by obesity have an increased risk of developing mood disorders. The relationship between obesity and mood disorders is bidirectional. We assessed whether a Hericium erinaceus treatment improved depression, anxiety, sleep, and binge eating disorders after 8 weeks of supplementation in subjects affected by overweight or obesity under a low calorie diet regimen. Looking for a possible clinical biomarker, we assessed the serum balance between brain-derived neurotrophic factor (BDNF) and its precursor pro-BDNF before and after H. erinaceus supplementation. Seventy-seven volunteers affected by overweight or obesity were recruited at the offices of the Department of Preventive Medicine, Luigi Devoto Clinic of Work, Obesity Centre, at the IRCCS Foundation Policlinico Hospital of Milan (Italy). Patients were recruited only if they had a mood and/or sleep disorder and/or were binge eating as evaluated through self-assessment questionnaires. We used two different enzyme-linked immunosorbent assays kits to discriminate circulating levels of pro-BDNF and BDNF. Eight weeks of oral H. erinaceus supplementation decreased depression, anxiety, and sleep disorders. H. erinaceus supplementation improved mood disorders of a depressive-anxious nature and the quality of the nocturnal rest. H. erinaceus increased circulating pro-BDNF levels without any significant change in BDNF circulating levels.
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Basidiomycetes of the genus Hericium are among the most praised medicinal and edible mushrooms, which are known to produce secondary metabolites with the potential to treat neurodegenerative diseases. This activity has been attributed to the discovery of various terpenoids that can stimulate the production of nerve growth factor (NGF) or (as established more recently) brain-derived neurotrophic factor (BDNF) in cell-based bioassays. The present study reports on the metabolite profiles of a Lion's Mane mushroom (Hericium erinaceus) strain and a strain of the rare species, Hericium flagellum (synonym H. alpestre). While we observed highly similar metabolite profiles between the two strains that were examined, we isolated two previously undescribed metabolites, given the trivial names erinacines Z1 and Z2. Their chemical structures were elucidated by means of nuclear magnetic resonance (NMR) spectroscopy and high resolution mass spectrometry. Along with six further, previously identified cyathane diterpenes, the novel erinacines were tested for neurotrophin inducing effects. We found that erinacines act on BDNF, which is a neurotrophic factor that has been reported recently by us to be induced by the corallocins, but as well on NGF expression, which is consistent with the literature.
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Antidepressant-like effects of ethanolic extract of Hericium erinaceus (HE) mycelium enriched in erinacine A on depressive mice challenged by repeated restraint stress (RS) were examined. HE at 100, 200 or 400 mg/kg body weight/day was orally given to mice for four weeks. After two weeks of HE administration, all mice except the control group went through with 14 days of RS protocol. Stressed mice exhibited various behavioral alterations, such as extending immobility time in the tail suspension test (TST) and forced swimming test (FST), and increasing the number of entries in open arm (POAE) and the time spent in the open arm (PTOA). Moreover, the levels of norepinephrine (NE), dopamine (DA) and serotonin (5-HT) were decreased in the stressed mice, while the levels of interleukin (IL)-6 and tumor necrosis factor (TNF)-α were increased. These changes were significantly inverted by the administration of HE, especially at the dose of 200 or 400 mg/kg body weight/day. Additionally, HE was shown to activate the BDNF/TrkB/PI3K/Akt/GSK-3β pathways and block the NF-κB signals in mice. Taken together, erinacine A-enriched HE mycelium could reverse the depressive-like behavior caused by RS and was accompanied by the modulation of monoamine neurotransmitters as well as pro-inflammatory cytokines, and regulation of BDNF pathways. Therefore, erinacine A-enriched HE mycelium could be an attractive agent for the treatment of depressive disorders.
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Versatile biological activities of Hericium erinaceus (HE) have been reported in many brain diseases. However, roles of HE in major psychiatric disorders such as depression and anxiety remain to be investigated. Therefore, we evaluated whether HE could reduce anxiety and depressive behaviors in the adult mouse and its underlying mechanisms. Male C57BL/6 mice were administered HE (20 or 60 mg/kg, p.o.) or saline once a day for 4 weeks. Open field and tail suspension tests were performed 30 min after the last administration of HE, followed by forced swim test 2 days later. We found that chronic administration of HE showed anxiolytic and antidepressant-like effects. To elucidate possible mechanisms, proliferative activity of the hippocampal progenitor cells was assessed by immunohistochemistry of proliferating cell nuclear antigen (PCNA) and Ki67. Moreover, to evaluate neuronal survival in the dentate gyrus, 5-bromo-2'-deoxyuridine (BrdU) (120 mg/kg, i.p.) was given at the first day of HE administration, followed by isolation of the brains 4 weeks later. HE (60 mg/kg) increased the number of PCNA- and Ki67-positive cells in the subgranular zone of the hippocampus, indicating increased proliferation of hippocampal progenitors. In addition, BrdU- and BrdU/NeuN-positive cells in the dentate gyrus were significantly increased when treated with HE (60 mg/kg) compared with the saline-treated group, demonstrating enhanced neurogenesis by HE treatment. Taken together, the results indicate that chronic HE administration can exert anxiolytic and antidepressant-like effects, possibly by enhancing adult hippocampal neurogenesis.
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Treatment-resistant depression is a major health problem worldwide. Restricted validity of the existing animal models of depression along with the need for the study of progressive development of resistance to antidepressants, demands the modeling of a progressive animal model of depression. Present study was designed to test the hypothesis that the repeated administration of reserpine could serve as a progressive animal model of depression. Animals were injected with reserpine (1.0mg/kg; once a day) for three weeks. Results from the present study showed impaired locomotive effects of reserpine in Skinner's box following second as well as third week. These hypolocomotive effects were more pronounced after third week than the second week. Reserpine-induced behavioral depression was evident in the animals after 2 weeks, as assessed by using forced swim test. Depletion of 5-HT, dopamine and metabolites was also observed in the brain samples. Results from the present study suggest that repeated administration of reserpine could be serve as a progressive model of depression and could be used as a convenient and economic animal model for the face validity of anxiolytic compounds. Findings have potential implications with reference to the understanding and the management of treatment-resistant depression.
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Background: Side effects play a key role in patients' failure to take antidepressants. There is evidence that verbal suggestions and informed consent elicit expectations that can in turn trigger the occurrence of side effects. Prior experience or learning mechanisms are also assumed to contribute to the development of side effects, although their role has not been thoroughly investigated. In this study, we examined whether an antidepressant's side effects can be learned via Pavlovian conditioning. Methods: Participants (n = 39) were randomly allocated to one of two groups and were exposed to a classical conditioning procedure. During acquisition, 19 participants received amitriptyline and 20 participants received a placebo pill. Pills were taken for four nights together with a novel-tasting drink. After a washout phase, both groups received a placebo pill together with the novel-tasting drink (evocation). Side effects were assessed via the Generic Assessment of Side Effects Scale prior to acquisition (baseline), after acquisition, and after evocation. A score of antidepressant-specific side effects was calculated. Results: Participants taking amitriptyline reported significantly more antidepressant-specific side effects after acquisition compared to both baseline and the placebo group. After evocation, participants who underwent the conditioning procedure with amitriptyline reported significantly more antidepressant-specific side effects than those who never received amitriptyline, even though both groups received a placebo. Conclusions: Our results indicate that antidepressant side effects can be learned using a conditioning paradigm and evoked via a placebo pill when applied with the same contextual factors as the verum.
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There is an increasing risk of mental disorders, such as acute stress disorder (ASD), post-traumatic stress disorder (PTSD) and depression among survivors who were trapped in rubble during earthquake. Such long-term impaction of a single acute restraint stress has not been extensively explored. In this study, we subjected mice to 24-hour-restraint to simulate the trapping episode, and investigated the acute (2 days after the restraint) and long-term (35 days after the restraint) impacts. Surprisingly, we found that the mice displayed depression-like behaviors, decreased glucose uptake in brain and reduced adult hippocampal neurogenesis 35 days after the restraint. Differential expression profiling based on microarrays suggested that genes and pathways related to depression and other mental disorders were differentially expressed in both PFC and hippocampus. Furthermore, the depression-like phenotypes induced by 24-hour-restraint could be reversed by fluoxetine, a type of antidepressant drug. These findings demonstrated that a single severe stressful event could produce long-term depressive-like phenotypes. Moreover, the 24-hour-restraint stress mice could also be used for further studies on mood disorders.
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Background The fruiting body of Hericium erinaceus has been demonstrated to possess anti-dementia activity in mouse model of Alzheimer’s disease and people with mild cognitive impairment. However, the therapeutic potential of Hericium erinaceus mycelia on Alzheimer’s disease remains unclear. In this study, the effects of erinacine A-enriched Hericium erinaceus mycelia (HE-My) on the pathological changes in APPswe/PS1dE9 transgenic mouse model of Alzheimer’s disease are studied. Results After a 30 day oral administration to 5 month-old female APPswe/PS1dE9 transgenic mice, we found that HE-My and its ethanol extracts (HE-Et) attenuated cerebral Aβ plaque burden. It’s worth noting that the attenuated portion of a plaque is the non-compact structure. The level of insulin-degrading enzyme was elevated by both HE-My and HE-Et in cerebral cortex. On the other hand, the number of plaque-activated microglia and astrocytes in cerebral cortex and hippocampus were diminished, the ratio of nerve growth factor (NGF) to NGF precursor (proNGF) was increased and hippocampal neurogenesis was promoted after these administrations. All the mentioned benefits of these administrations may therefore improve the declined activity of daily living skill in APPswe/PS1dE9 transgenic mice. Conclusions These results highlight the therapeutic potential of HE-My and HE-Et on Alzheimer’s disease. Therefore, the effective components of HE-My and HE-Et are worth to be developed to become a therapeutic drug for Alzheimer’s disease.
Objective: To conduct a systematic review and meta-analysis of studies that measured cytokine and chemokine levels in individuals with major depressive disorder (MDD) compared to healthy controls (HCs). Method: The PubMed/MEDLINE, EMBASE, and PsycINFO databases were searched up until May 30, 2016. Effect sizes were estimated with random-effects models. Result: Eighty-two studies comprising 3212 participants with MDD and 2798 HCs met inclusion criteria. Peripheral levels of interleukin-6 (IL-6), tumor necrosis factor (TNF)-alpha, IL-10, the soluble IL-2 receptor, C-C chemokine ligand 2, IL-13, IL-18, IL-12, the IL-1 receptor antagonist, and the soluble TNF receptor 2 were elevated in patients with MDD compared to HCs, whereas interferon-gamma levels were lower in MDD (Hedge's g = -0.477, P = 0.043). Levels of IL-1β, IL-2, IL-4, IL-8, the soluble IL-6 receptor (sIL-6R), IL-5, CCL-3, IL-17, and transforming growth factor-beta 1 were not significantly altered in individuals with MDD compared to HCs. Heterogeneity was large (I(2) : 51.6-97.7%), and sources of heterogeneity were explored (e.g., age, smoking status, and body mass index). Conclusion: Our results further characterize a cytokine/chemokine profile associated with MDD. Future studies are warranted to further elucidate sources of heterogeneity, as well as biosignature cytokines secreted by other immune cells.