Glossary of studies on Hericium erinaceus (Lion’s

mane mushroom)

Prevention of Early Alzheimer's Disease by Erinacine A-Enriched Hericium

erinaceus Mycelia Pilot Double-Blind Placebo-Controlled Study

Objective: To investigate the efficacy and safety of three H. erinaceus mycelia (EAHE)
capsules (350 mg/capsule; containing 5 mg/g erinacine A active ingredient) per day
for the treatment of patients with mild Alzheimer's Disease (AD).

Methods: This study comprised a 3-week no-drug screening period, followed by a 49-
week double-blind treatment period with 2-parallel groups in which eligible patients
were randomized to either three 5 mg/g EAHE mycelia capsules per day or identical
appearing placebo capsules. Cognitive assessments, ophthalmic examinations,
biomarker collection, and neuroimaging were followed throughout the study period.

Results: After 49 weeks of EAHE intervention, a significant decrease in Cognitive

Abilities Screening Instrument score was noted in the placebo group, a significant
improvement in Mini-Mental State Examination score was observed in the EAHE group
and a significant Instrumental Activities of Daily Living score difference were found
between the two groups. In addition, EAHE group achieved a significantly better
contrast sensitivity when compared to the placebo group. Moreover, only the placebo
group observed significantly lowered biomarkers such as calcium, albumin,
apolipoprotein E4, hemoglobin, and brain-derived neurotrophic factor and
significantly elevated alpha1-antichymotrypsin and amyloid-beta peptide 1-40 over
the study period. Using diffusion tensor imaging, the mean apparent diffusion
coefficient (ADC) values from the arcuate fasciculus region in the dominant
hemisphere significantly increased in the placebo group while no significant difference
was found in the EAHE group in comparison to their baselines. Moreover, ADC values
from the parahippocampal cingulum region in the dominant hemisphere significantly
decreased in the EAHE group whereas no significant difference was found in the
placebo group when compared to their baselines. Lastly, except for four subjects who
dropped out of the study due to abdominal discomfort, nausea, and skin rash, no other
adverse events were reported.

Conclusion: Three 350 mg/g EAHE capsules intervention for 49 weeks demonstrated
higher CASI, MMSE, and IADL scores and achieved a better contrast sensitivity in

D-27, Sector 80, Noida, U4ar Pradesh 201306

patients with mild AD when compared to the placebo group, suggesting that EAHE is
safe, well-tolerated, and may be important in achieving neurocognitive benefits.

Clinical trial registration: ClinicalTrials.gov, identifier NCT04065061.

Structural characterization of polysaccharide purified from Hericium erinaceus

fermented mycelium and its pharmacological basis for application in Alzheimer's
disease: Oxidative stress related calcium homeostasis

Abstract

The purified polysaccharides from Hericium erinaceus fermented mycelium entitled

with PHEB was analyzed and it was mainly composed of six glycosidic bonds. It has
been confirmed to show the relieving activity against Alzheimer's Disease (AD)- just as
behaviors of B6C3-Tg (APPswePSEN1d E9)/Nju double transgenic [Genotype:
(Appswe)T, (Psen1) T] (APP/PS1) mice. Six-week PHEB administration significantly
improved the cognitive behavior of mice. Brain injury, amyloid beta deposition and tau
hyperphosphorylation were alleviated in PHEB-treated AD mice without changes in
other tissues. PHEB alleviated the oxidative stress in brains of AD mice via regulation
the Nrf2 and its downstream kinase, which further improved the cholinergic system
function. Proteomics and bioinformatics analysis showed that the therapeutic effect of
PHEB is achieved by regulating calcium homeostasis mediated by oxidative stress.
Furthermore, PHEB regulated the CaMK II/IV to achieve the calcium homeostasis in
brains; and ultimately to show the anti-AD property.

D-27, Sector 80, Noida, U4ar Pradesh 201306

Erinacine A-enriched Hericium erinaceus mycelium ameliorates Alzheimer's
disease-related pathologies in APPswe/PS1dE9 transgenic mice

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.

D-27, Sector 80, Noida, U4ar Pradesh 201306

Improving effects of the mushroom Yamabushitake (Hericium
erinaceus) on mild cognitive impairment: a double-blind placebo-
controlled clinical trial.
https://onlinelibrary.wiley.com/doi/abs/10.1002/ptr.2634

Abstract

A double-blind, parallel-group, placebo-controlled trial was performed on 50- to

80-year-old Japanese men and women diagnosed with mild cognitive impairment
in order to examine the efficacy of oral administration of Yamabushitake
(Hericium erinaceus), an edible mushroom, for improving cognitive impairment,
using a cognitive function scale based on the Revised Hasegawa Dementia Scale
(HDS-R). After 2 weeks of preliminary examination, 30 subjects were
randomized into two 15-person groups, one of which was given Yamabushitake
and the other given a placebo. The subjects of the Yamabushitake group took four
250 mg tablets containing 96% of Yamabushitake dry powder three times a day
for 16 weeks. After termination of the intake, the subjects were observed for the
next 4 weeks. At weeks 8, 12 and 16 of the trial, the Yamabushitake group
showed significantly increased scores on the cognitive function scale compared
with the placebo group. The Yamabushitake group's scores increased with the
duration of intake, but at week 4 after the termination of the 16 weeks intake, the
scores decreased significantly. Laboratory tests showed no adverse effect of
Yamabushitake. The results obtained in this study suggest that Yamabushitake is
effective in improving mild cognitive impairment.

D-27, Sector 80, Noida, U4ar Pradesh 201306

Effects of erinacine A-enriched Hericium erinaceus on elderly
hearing-impaired patients: A double-blind, randomized, placebo-
controlled clinical trial

https://www.sciencedirect.com/science/article/pii/S175646462200290
0

Abstract
We aimed to investigate the effects and mechanisms of Hericium erinaceus (HE)
on hearing degeneration. By a double-blind, randomized, clinical trial, all 80
hearing-impaired patients aged 50–79 were randomly divided into the two
groups, which received HE mycelia (2000 mg/day) and placebo boluses for eight
months, respectively. A student’s t-test was used to evaluate the differences of
the average pure tone hearing threshold of all, low, and high frequencies (PTA-
all, PTA-low, and PTA-high); speech recognition threshold (SRT); speech
discrimination score (SDS); and serum concentrations of brain-derived
neurotrophic factor (BDNF) and neurotrophic growth factor (NGF) between the
two study groups. Subgroup analysis by age showed that PTA-high-Right, PTA-
all-Left, PTA-high-Left, SRT-Right, SRT-Left, and NGF were significantly
different between the two groups among patients aged ≧ 65. HE mycelia
treatment could ameliorate hearing loss, especially for high frequencies and
speech recognition, and increase NGF in patients aged ≧ 65.

D-27, Sector 80, Noida, U4ar Pradesh 201306

Hericium erinaceus in Neurodegenerative Diseases: From Bench to
Bedside and Beyond, How Far from the Shoreline?

https://www.mdpi.com/2309-608X/9/5/551

Abstract
A growing number of studies is focusing on the pharmacology and feasibility of
bioactive compounds as a novel valuable approach to target a variety of human
diseases related to neurological degeneration. Among the group of the so-called
medicinal mushrooms (MMs), Hericium erinaceus has become one of the most
promising candidates. In fact, some of the bioactive compounds extracted
from H. erinaceus have been shown to recover, or at least ameliorate, a wide
range of pathological brain conditions such as Alzheimer’s disease, depression,
Parkinson’s disease, and spinal cord injury. In a large body of in vitro and in vivo
preclinical studies on the central nervous system (CNS), the effects of erinacines
have been correlated with a significant increase in the production of neurotrophic
factors. Despite the promising outcome of preclinical investigations, only a
limited number of clinical trials have been carried out so far in different
neurological conditions. In this survey, we summarized the current state of
knowledge on H. erinaceus dietary supplementation and its therapeutic potential
in clinical settings. The bulk collected evidence underlies the urgent need to carry
out further/wider clinical trials to prove the safety and efficacy
of H. erinaceus supplementation, offering significant neuroprotective
applications in brain pathologies.

D-27, Sector 80, Noida, U4ar Pradesh 201306

Neurohealth Properties of Hericium erinaceus Mycelia Enriched
with Erinacines

https://www.hindawi.com/journals/bn/2018/5802634/
Abstract
Hericium erinaceus, an ideal culinary-medicinal mushroom, has become a well-
established candidate in promoting positive brain and nerve health-related
activities by inducing the nerve growth factor from its bioactive ingredient.
Among its active compounds, only erinacine A has confirmed pharmacological
actions in the central nervous system in rats. Hence, this review has summarized
the available information on the neurohealth properties of H. erinaceus mycelia
enriched with erinacines, which may contribute to further research on the
therapeutic roles of these mycelia. The safety of this mushroom has also been
discussed. Although it has been difficult to extrapolate the in vivo studies to
clinical situations, preclinical studies have shown that there can be improvements
in ischemic stroke, Parkinson’s disease, Alzheimer’s disease, and depression if H.
erinaceus mycelia enriched with erinacines are included in daily meals.

D-27, Sector 80, Noida, U4ar Pradesh 201306

Hericium erinaceus Improves Recognition Memory and Induces Hippocampal
and Cerebellar Neurogenesis in Frail Mice during Aging

Abstract

Frailty is a geriatric syndrome associated with both locomotor and cognitive decline,
implicated in both poor quality of life and negative health outcomes. One central
question surrounding frailty is whether phenotypic frailty is associated with the
cognitive impairment during aging. Using spontaneous behavioral tests and by
studying the dynamic change during aging, we demonstrated that the two form of
vulnerability, locomotor and recognition memory decline, develop in parallel and
therefore, integration of the motoric and cognitive evaluations are imperative. We
developed an integrated frailty index based on both phenotypic and recognition
memory performances. Hericium erinaceus (H. erinaceus) is a medicinal mushroom
that improves recognition memory in mice. By using HPLC-UV-ESI/MS analyses we
obtained standardized amounts of erinacine A and hericenones C and D in H.
erinaceus extracts, that were tested in our animal model of physiological aging. Two-
month oral supplementation with H. erinaceus reversed the age-decline of recognition
memory. Proliferating cell nuclear antigen (PCNA) and doublecortin (DCX)
immunohistochemistry in the hippocampus and cerebellum in treated mice supported
a positive effect of an H. erinaceus on neurogenesis in frail mice.

The Monkey Head Mushroom and Memory Enhancement in Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder, and no effective treatments

are available to treat this disorder. Therefore, researchers have been
investigating Hericium erinaceus, or the monkey head mushroom, an edible medicinal
mushroom, as a possible treatment for AD. In this narrative review, we evaluated six
preclinical and three clinical studies of the therapeutic effects of Hericium erinaceus on
AD. Preclinical trials have successfully demonstrated that extracts and bioactive
compounds of Hericium erinaceus have potential beneficial effects in ameliorating
cognitive functioning and behavioral deficits in animal models of AD. A limited number
of clinical studies have been conducted and several clinical trials are ongoing, which
have thus far shown analogous outcomes to the preclinical studies. Nonetheless,
future research on Hericium erinaceus needs to focus on elucidating the specific
neuroprotective mechanisms and the target sites in AD. Additionally, standardized
treatment parameters and universal regulatory systems need to be established to

D-27, Sector 80, Noida, U4ar Pradesh 201306

further ensure treatment safety and efficacy. In conclusion, Hericium erinaceus has
therapeutic potential and may facilitate memory enhancement in patients with AD.

Neuroprotective Metabolites of Hericium erinaceus Promote Neuro-Healthy

Aging

Frailty is a geriatric syndrome associated with both locomotor and cognitive decline,
typically linked to chronic systemic inflammation, i.e., inflammaging. In the current
study, we investigated the effect of a two-month oral supplementation with
standardized extracts of H. erinaceus, containing a known amount of Erinacine A,
Hericenone C, Hericenone D, and L-ergothioneine, on locomotor frailty and
cerebellum of aged mice. Locomotor performances were monitored comparing
healthy aging and frail mice. Cerebellar volume and cytoarchitecture, together with
inflammatory and oxidative stress pathways, were assessed focusing on senescent frail
animals. H. erinaceus partially recovered the aged-related decline of locomotor
performances. Histopathological analyses paralleled by immunocytochemical
evaluation of specific molecules strengthened the neuroprotective role of H.
erinaceus able to ameliorate cerebellar alterations, i.e., milder volume reduction,
slighter molecular layer thickness decrease and minor percentage of shrunken Purkinje
neurons, also diminishing inflammation and oxidative stress in frail mice while
increasing a key longevity regulator and a neuroprotective molecule. Thus, our present
findings demonstrated the efficacy of a non-pharmacological approach, based on the
dietary supplementation using H. erinaceus extract, which represent a promising
adjuvant therapy to be associated with conventional geriatric treatments.

Improvement of cognitive functions by oral intake of Hericium erinaceus

Abstract

Hericium erinaceus has been recognized as medical mushroom since ancient time, but
its scientific evidence for human health has been still uncertain. In this study, we tested
a randomized, double-blind, placebo-controlled parallel-group comparative study to
evaluate the improvement of the cognitive functions by taking supplements
containing fruiting body of H. erinaceus for 12 weeks. We performed three kinds of
tests: Mini Mental State Examination (MMSE), Benton visual retention test, and
Standard verbal paired-associate learning test (S-PA). MMSE alone showed that oral
intake of H. erinaceus significantly improved cognitive functions and prevented from
the deterioration. We speculate that various chemical compounds, including
hericenones, in the mushroom have multiple effects to the brain neural networks and

D-27, Sector 80, Noida, U4ar Pradesh 201306

improve cognitive functions. Oral intake of H.erinaceus is safe and convenient method
for dementia prevention so far.

D-27, Sector 80, Noida, U4ar Pradesh 201306