Accepted Manuscript

Pharmacological effects of natural Ganoderma and its extracts onneurological diseases: A comprehensive review

Chen Zhao, Chunchen Zhang, Zheng Xing, Zeeshan Ahmad, Jing-Song Li, Ming-Wei Chang

PII: S0141-8130(18)34479-9DOI: doi:10.1016/j.ijbiomac.2018.10.076Reference: BIOMAC 10727

To appear in: International Journal of Biological Macromolecules

Received date: 25 August 2018Revised date: 6 October 2018Accepted date: 14 October 2018

Please cite this article as: Chen Zhao, Chunchen Zhang, Zheng Xing, Zeeshan Ahmad,Jing-Song Li, Ming-Wei Chang , Pharmacological effects of natural Ganoderma and itsextracts on neurological diseases: A comprehensive review. Biomac (2018), doi:10.1016/j.ijbiomac.2018.10.076

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Pharmacological Effects of Natural Ganoderma and Its Extracts on Neurological

Diseases: A Comprehensive Review

Chen Zhao a,c, Chunchen Zhang a,, Zheng Xing c, Zeeshan Ahmad d, Jing-

Song Li a, Ming- Wei Chang a,b,*

aKey Laboratory for Biomedical Engineering of Education Ministry of China,

Zhejiang University, Hang Zhou, 310027, PR China.

bZhejiang Provincial Key Laboratory of Cardio Cerebral Vascular Detection Technology and

Medicinal Effectiveness Appraisal, Zhejiang University, Hangzhou,310027, PR China

cDepartment of Pharmacology, Shenyang Pharmaceutical University, Shenyang, 110000, PR China.

dLeicester School of Pharmacy, De Montfort, University, The Gateway, Leicester, LE1 9BH, UK.

*Corresponding author: Ming-Wei Chang, Ph.D., Assoc. Professor

Tel: +86(0)571-87951517, Email: mwchang@zju.edu.cn

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Abstract：Ganoderma, has been used for clinical applications for thousands of years

as a highly-nutritious and significantly-effective medicinal herb. The active

components and efficacy of Ganoderma are constantly being explored and

supplemented every year. In recent years, more and more literature has reported the

pharmacological effects of Ganoderma on anti-tumor, liver protection and immunity

enhancement, especially on neuroprotection. Numerous research works on the

neuroprotective effects of Ganoderma have been documented (e.g., modulation of

neurogenesis, amelioration of Alzheimer's disease, therapeutic effect on epilepsy, the

protective effect on neural cells in stroke injury, etc.) thus it has drawn increasing

attention. However, an integrated and comprehensive review of recent research findings

has not been detailed in any great depth. Therefore, the purpose of this review is to

summarize and elucidate recent progress of neuroprotective effects of natural

Ganoderma and its extracts.

Keywords: Traditional Chinese Medicine; Ganoderma; neurological diseases.

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Abbreviations: AD, Alzheimer’s disease; Cdk2, cyclin-dependent protein kinase 2;

Cdk4, cyclin-dependent protein kinase 4; CGI, Clinical Global Impression; CRF,

Cancer-related fatigue; CVD, Cerebrovascular disease; DOI, (±)-1-(2,5-dimethoxy-4-

iodo-phenyl)-2-aminopropane hydrochloride; FST, forced swimming test; GLA, G.

lucidum aqueous extract; GLP, G. lucidum polysaccharides; GLS, G. lucidum spore;

GS, Ganoderma total sterol; H/R, hypoxia/reoxygenation; MAK, G. lucidum mycelia;

MDA, malondialdehyde; NTDs, Neural tube defects; OFT, open-field test; PD,

Parkinson's disease; REM, rapid eye movement; SCI, Spinal cord injury; TCM,

Traditional Chinese Medicine; TH, Tyrosine hydroxylase; TNF-α, Tumor Necrosis

Factor alpha; TST, Tail suspension test; VAS, Visual Analogue Scale; VASwb, Visual

Analogue Scale for well-being; 5-HT, 5-hydroxytryptamine;

1. Introduction

Traditional Chinese Medicine (TCM) refers to medicinal materials used for

prevention and treatment of diseases as well as rehabilitation and healthcare purposes.

TCM including plant medicine, animal products [1], mineral medicine and some

chemical and biological products, are mainly obtained from natural medicine and its

processed (Pao Zhi) products. As early as the Yellow Emperor's Inner Canon and Sheng

Nong's Herbal Classic, two of the most influential Chinese traditional medicine books,

the pharmacological effects and utilizing methods of TCM has been described in detail,

which has been relied on for thousands of years by the Chinese and other Asian people

[2]. In 1971, a nontoxic neutral extract, namely, artemisinin was extracted from

Artemisia annua by Tu et al. using ether as solvent. Its cure rate for mice infected with

Plasmodium berghei and monkeys infected with Plasmodium cynomolgi was 100

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percent [3]. As a result of this important discovery; millions of lives around the world

have been saved, especially in developing countries [4]. For his achievements, Youyou

Tu won the 2015 Nobel Prize in Physiology or Medicine. Conventional dosage forms

of TCM include decoctions, dispersants, tablets/capsules, suppositories, lotions,

fumigant and liquor [5]. There are 365 types of TCM recorded in Shen Nong’s Herbal

Classic, and 8,880 types of TCM are recorded in the latest Chinese Materia Medica

(1999). Among them, the most widely used are Ganoderma, Panax ginseng [6-8],

Astragalus membranaceus [9-12], Panax notoginseng [13-15], green tea, Herba

Epimedii [16], Berberine [17], Scutellaria [18], Aconitum [19], Ginkgo biloba etc. [20].

These TCM have certain therapeutic protective effects on diseases of the nervous

system such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and cerebral

ischemia [21]. According to our survey, Ganoderma is the most widely used and most

studied of these making it a front runner in TCM.

Ganoderma, also known as Ling-Zhi in Chinese and Reishi in Japanese. Fruiting

bodies and spores of Ganoderma (Leyss. ex Fr.) Karst have been used for thousands of

years as TCM mainly in Asian areas including China, Japan and Korea [22]. As

recorded in the Shen Nong's Herbal Classic (Shen Nong Ben Cao Jing), which is the

source of the development of TCM pharmacology theory and collected by many

Chinese medical scientists in the Qin and Han dynasties, Ganoderma had the efficacy

of improving immunity, soothing the nerves, helping sleep, protecting the liver,

detoxification, anti-aging and prolonging life expectancy [23]. Ganoderma depending

on color can be divided into lucidum, black, green, white, yellow, purple Chi. Among

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them, Ganoderma lucidum (G. lucidum) was the most widely used, followed by

Ganoderma applanatum (G. applanatum), Ganoderma tsugae (G. tsugae) and

Ganoderma capense (G. capense) [24]. More recently, the pharmacological effects of

Ganoderma have attracted considerable attention from the global research community.

In addition, Ganoderma has the effects of anti-aging [22], anti-tumor [25], curing

neurasthenia [26], anti-diabetic [27], anti-heart failure [28], treating hepatitis [29] and

so on. The active ingredients extracted from fruiting bodies include polysaccharides,

triterpenoids, ganoderic acids, alkaloids, fatty acids, organic germanium, ergosterol

[30]. Except for the constituents mentioned above, spores also contain mannitol,

trehalas and the like. Methods of breaking G. lucidum protoderm are enzymatic

methods [31], physical grinding [32], supercritical CO2 processing [33], ice-assisted

sonication etc. [34].

Fig. 1 shows the number of papers on the neuroprotective effects of components

extracted from Ganoderma published from 2000 to 2017. It can be seen that there has

been a surge of literature since 2000, culminating in 2009 and cooling off after about 5

years of research, but since 2014, the number of reports on the protective role of G.

lucidum has been on a clear upward trend, which indicates that the research in this field

is more and more extensive and profound. In addition, the most studied extract is

Ganoderma polysaccharide, followed by triterpenoids, and other extracts. From this we

can foresee that in 2018, the number of related articles will be higher than that of 2017

and continue increasing.

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Fig. 1. The number of papers on the neuroprotective effects of components extracted

from Ganoderma.

Neurological disorders are affecting an increasing number of people worldwide,

every age group is at a risk of suffering from neurological disorders from infants to

adults to the elderly [35, 36]. Neurological diseases include degenerative diseases such

as Alzheimer's disease (AD) and Parkinson's Disease (PD), and other neurological

diseases including stroke, epilepsy, Spinal Cord Injury (SCI) and Neural Tube Defects

(NTD) etc. [37, 38]. Fig. 2 shows the number of articles on the therapeutic effects of

Ganoderma and its extract on various neurological diseases since 2000. By entering the

keywords "+ ganoderma" and "+ Alzheimer's disease" or other neurological diseases in

Google Scholar, a total of more than 3400 articles can be found, of which the number

of articles on the relationship between G. lucidum and CVD and epilepsy account for

the majority, with more than 600 articles or 20% each, followed by PD, AD,

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neurasthenia, SCI, neurogenesis, depression and NTD.

Fig. 2. The number of articles on the therapeutic effects of Ganoderma and its extract

on various neurological diseases

Being natural products TCM is associated with minimal side effects and cost-

effectiveness, which is beneficial for further developing the Chinese medicine industry.

As shown in Fig. 3, M1 is a metabolite of ginsenoside Rb1 [39]. After 14 consecutive

days with continuous oral administration of M1 and Rb1 in an AD mouse model the

mice in the administration group had improved spatial memory significantly and

reversed the reduction of NF-H (axonal marker), synaptophysin (synaptic marker), and

MAP2 significantly, compared with the control group, due to Aβ (25–35) in the brain.

All these results indicated a promising therapeutic effect of Panax ginseng on

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Alzheimer’s disease [40]. 6-hydroxydopamine (6-OHDA) is an oxidized metabolite of

dopamine, which may enter dopaminergic neurons via dopamine transporters (DAT) or

norepinephrine transporters (NAT) and give rise to oxidative stress and leading to cell

death as well as dopamine-like symptoms [41]. Astragaloside IV (AS-IV) is a small

molecular (MW784) saponin suggesting that AS-IV pretreatment significantly and

dose-dependently improved the 6-OHDA-induced loss of dopaminergic neurons,

rescued (TH)-immunopositive cells and facilitated normal neurite outgrowth in the

treatment of Parkinson's disease [11]. Panaxatriol saponin (PTS) is one of the main

bioactive components that pretreatment of low doses of PTS to P12 cells 24 hours in

advance could significantly reduce 6-OHDA-induced cell death by activating the AKT

and SIRT1 signaling pathways. All these results illustrated the neuroprotection of

Panax notoginseng extracts on Parkinson's disease [42]. Icariin is one of main

components derived from Herba Epimedii. Oral administration of Icariin with a purity

of more than 99.95% promoted neurogenesis by activating resting stem cells into the

neurogenesis lineage, explaining the potential benefit of this drug for Alzheimer's

disease [43].

Several studies have indicated that natural Ganoderma and its extraction exhibit

protective function of neural system diseases through a variety of mechanisms. This

review summarizes and discusses the therapeutic and protective effects of natural

Ganoderma and its extracts on neural system diseases to benefit scholars from different

fields and encourage more and more researchers to conduct a more in-depth and clinical

study on Ganoderma, a TCM which has been used for thousands of years.

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TCM Active constituents Neuroprotection Ref

[40]

[44]

[45]

[10]

[11]

[12]

[15]

[14]

[46]

[47]

[48]

[49]

Fig. 3. Other TCM and their neuroprotection.

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2. Ganoderma and its extracts

2.1 Classification of Ganoderma

Gen. Ganoderma was established by Karsten in 1881 [50], including only one

species (Ganoderma lucidum) at that time. In 1889, Patouillardzai divided the

Ganoderma into Section Ganoderma and Section Amauroderma [51]. In the same year,

Karsten established Elfvingia [52]. In 1933, Donk promoted Ganoderma to

Ganodermoideae [53]. With the continuous exploration and improvement, there are at

least 60 species of Gen. Ganoderma, 45 species of Gen. Amauroderma and 6 species

of Gen. Elfvingia, accounting for about 111 species with more than 300 names [54].

The Ganoderma classification diagram is shown in Fig. 4 Among them, six are the most

detailed and most commonly used, containing lucidum, applanatum, sinense, tsugae,

capense, boinense. This section mainly introduces the lucidum, tsugae and applanatum,

which are the most widely studied of these. Their characteristics and applications are

described as follows.

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Fig. 4. Classification diagram of Ganoderma [55]. Ganoderma can be divided into Gen.

Ganoderma Karst and Gen. Amauroderma. The former can be divided into Subsect.

Ganoderma and Subsect. Trachyderma. According to whether the spore wall contain

obvious small spines, Subsect. Ganoderma can be divided Ganoderma lucidum,

Ganoderma tsugae, Ganoderma capense and so on.

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2.1.1. G. lucidum

The earliest record dates of G. lucidum can be traced back to 1781 and its

specimen was collected by Curtis at Peckham, in the south of England [56]. Its main

feature is that the fungi cover and fungi surface has a red-brown paint-like luster, spores

oval, light brown, bilateral spore wall, the outer wall is transparent and smooth, while

the inner wall with fine spines, is currently the main types of cultivation and application

[57]. The commonly known Ganoderma is G. lucidum. Its coverage and research are

also the most comprehensive and in-depth since lucidum and has shown an effect for

anti-cancer [58], anti-inflammatory [59], anti-oxidant [60], neuroprotection and liver

protecting purposes, as well as enhancing the immunity system [61].

2.1.2. G. tsugae

The origin of the sample is in the United States, with a similar shape as G. lucidum,

and a paint-like luster on surface. The difference between tsugae and lucidum is that

the latter is usually saprophytic on broad-leaved trees, but the former is saprophytic on

conifers [62]. It is reported that G. tsugae has anti-cancer [63]. and anti-inflammatory

effects [64].

2.1.3. G. applanatum

G. applanatum specimen is of European origin and is found in all parts of the world.

It can grow up to a width of 40 cm or longer, with neither a handle in fruiting body nor

a paint-like luster on the surface. It is generally used with wild fruiting bodies, but some

people have used it to carry out deep fermentation to make Reishi tea or wine [65]. G.

applanatum is reported to have an inhibitory effect on certain cancers [66] as well

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providing an anti-inflammatory [67] and anti-fibrotic [68] effect.

2.2 Extraction of active chemical components from Ganoderma

The purpose of the extraction is to isolate the active compounds from the fruiting

body or spores of Ganoderma to the maximum extent with the least possible loss or

waste, thus allowing the active compounds to be applied for the treatment or prevention

of certain diseases. The general extraction process can be divided into physical mode,

chemical mode, biological enzyme mode and mixed mode. The commonly used

extraction processes include water extraction, organic solvent extraction, enzymatic

extraction, ultrasonic extraction, microwave extraction, alkali extraction, ultrafiltration

membrane extraction, superfine grinding technology, steam explosion technology, and

the like. In the extraction process, the type, polarity and amount of extracts need to be

considered, so that the extraction methods can be selected appropriately. The literature

reports on several Ganoderma extracts are described here.

2.2.1 solvent extraction

A common method for extracting polysaccharides from Ganoderma is water

extraction combined with alcohol precipitation [69]. Dilute acid, dilute alkali, and dilute

salts can also be used for extraction [70]. Solvent Extraction of the active ingredients

from Ganoderma are mainly based on the polarity of the solvent and the extracts [71].

The hot water as a solvent extraction method utilizes the water solubility of

polysaccharides to extract it [72]. The ratio of material/solution, extraction temperature

and extraction time are all factors that result in final yield. The findings of Huang et al.

indicated that the optimal extraction temperature was 60.1 °C, the best extraction time

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was 77.3 min, and the optimal substrate/liquid ratio was 1:21.4 [73]. Although this

method is simple and convenient, only extracellular polysaccharides can generally be

extracted because of the cellular nature of the plant, so that the extraction rate is low,

and long-term high temperatures may degrade polysaccharides and reduce the

biological activity of polysaccharides [74]. The extraction methods of G. lucidum

triterpenes include organic solvent extraction, alkali acid extraction and chloroform

extraction [75, 76]. As shown in Fig. 5, through this extraction method, polysaccharides,

triterpenes, selenium and proteins in Ganoderma can be extracted.

2.2.2. Ultrasonic assisted extraction

The combination of ultrasonic technology and extraction process can increase the

yield and reduce the extraction time. Ultrasonic assisted extraction has the

characteristics of excellent directionality and strong penetrability. Ultrasound can break

cell walls and cell membranes of medicinal materials through cavitation effect,

mechanical effect and thermal effect, thus the solvent penetrates into the cells of the

medicinal material or the intracellular chemical components are diffused out of the cells,

so that more intracellular components are dissolved [77]. Then the solvent is separated

and purified to obtain the desired active ingredients. There are several reports on the

use of ultrasound to enhance the extraction of polysaccharides [78, 79]. Ultrasound can

give rise to the violent vibration of liquid particles, known as cavitation, which can

result in the collapse of the cell wall and changes in the function of cells, allowing

intracellular substances to enter the solvent rapidly [80]. The ultrasonication time,

ultrasonic power, temperature, solvent dosage and other parameters all affect the

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extraction efficiency of Ganoderma active constituents [79]. Fig. 5 shows that with this

extraction method, polysaccharides and sterols in Ganoderma can be extracted.

2.2.3. Microwave extraction

The microwave extraction method utilizes microwave radiation and vibration to

make polar substances absorb energy to generate heat and destroy plant cell walls to

release intracellular substances [81]. With a strong penetrating power, the microwave

method can uniformly and rapidly heat substances of both inside and outside, thus the

yield is high. Song et al used a vacuum-microwave radiation method to get

polysaccharides from G. lucidum and found that the yield reached 1.775%, which was

48.1% higher than that of hot water extraction, and the extraction time was shortened

by more than a half [82]. Infiltration time, microwave power density and radiation time

all could affect the final yield [80]. The microwave method can be used to heat different

components selectively and heat quickly, so it has the advantages of high selectivity,

shorter time and less pollutants. By this extraction method, polysaccharides and

triterpenes in Ganoderma are adapted for extraction.

2.2.4. Superfine grinding technology

Ultrafine crushing refers to the use of mechanical or hydrodynamic methods to

overcome the solid internal cohesion and crush it, thereby crushing material particles

(diameter over 3 mm) to 10 to 25 μm. Ultrafine powders are the ultimate products of

ultrafine grinding, possessing special physical and chemical properties that are not

found in general particles, such as good solubility, dispersibility, adsorption, and

chemical reactivity. For this reason, ultra-fine powder has been widely used in many

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fields such as food [83], chemical [84], mining [85], pharmaceutical [86], cosmetics

[87], electronics [88] and aerospace. By this extraction method, polysaccharides and

triterpenes in Ganoderma can be obtained [89].

2.2.5. Steam explosion technology

Steam explosion technology uses steam to heat the raw material to 160–260 °C and

0.69–4.83 MPa [90]. The pressure is maintained for a few seconds to several minutes

before the pressure is released [91]. When the pressure is reduced, secondary steam is

generated and the gas rapidly expands. The solid material structure is damaged due to

the mechanical force and then low molecular weight substances in Ganoderma can be

obtained [92].

The response surface methodology contains statistical and mathematical techniques

used in different extraction methods that reflect the relationship between multiple input

variables and output values of chemical processes, reducing the number of experimental

tests required to evaluate multiple parameters and their interactions, and generates a

function model to find the best response value [93]. Therefore, applying it to ultrafine

grinding or a water extraction process for extracting GLP can make the arrangement of

experimental conditions more efficient and reasonable [74, 89].

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Fig. 5. Extraction methods and active chemical components of Ganoderma. The boxes

in the left column are the types of Ganoderma extracts. The boxes in the right column

are the extraction methods. Through these extraction methods, different kinds of

Ganoderma extracts can be obtained.

2.3. Chemical compounds of Ganoderma and its extracts

Since Japanese scientist Kubota reported the first triterpenoids ganoderic acid A

[94], researchers have extracted more than 400 active chemical constituents from the

mycelium, spores and fruiting bodies of Ganoderma [95], including triterpenoids,

polysaccharides, proteins, amino acids, nucleosides, nucleic acid, steroids, lactones,

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fatty acids, organic germanium, selenium, enzymes and alkaloids. Analysis of non-

volatile components of G. lucidum showed that it consists of several elements

including ash 0.72-1.77%, carbohydrate 21.83–27.78%, fat 1.1–8.3%, fiber 59-65%,

protein 7-8% and so on [96]. Among them, the most used and important chemical

components are Ganoderma polysaccharides, triterpenoids, and proteins.

2.3.1. Polysaccharides

G. lucidum polysaccharide (GLP) is one of the most important active components of

G. lucidum. Although the chemical structure of GLP varies with the kind of G. lucidum,

the types of monosaccharides that compose GLP are similar, including D-glucose, D-

fructose, D-galactose, D-mannose and D-xylose and so on [97]. The monosaccharides

are connected with β-(1→3) and β-(1→4) glycosidic bonds in the main chain, and the

branches are connected with β-(1→6) glycosidic bonds [97]. Exopolysaccharides can

be directly extracted, while the intra-spore polysaccharides need to break spores before

they can be extracted. The main extraction methods are hot water extraction, dilute

alkali extraction and ultrasonic extraction. Hu et al compared hot water extraction with

ultrasonic extraction to prove that the ultrasonic method shortened the extraction time

by 3/4 but increased the extraction rate by 30% [80]. By measuring the survival rate of

different groups of mice, Pillai et al found that GLPs had a significant protective effect

against radiation-induced damage [98]. GLP extracted from G. lucidum fruiting body

has a good antioxidant activity through free radicals scavenging and Fe2+ chelating [99].

Zhao et al. reported that GLP could significantly increase macrophage proliferation and

pinocytosis through MTT assay and plays an inhibitory effect on cancer cells by

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promoting the secretion of anti-tumor cytokines in macrophages [100]. Skalicka-

Woźniak et al used the micro-dilution broth method to determine the antibacterial

activity of the polysaccharides extracted from G. lucidum fruiting bodies grown in

different types of sawdust and demonstrated that all the polysaccharide samples have a

broad spectrum of antibacterial activity [101].

2.3.2. Triterpenoids

Ganoderma triterpene is one of the most important G. lucidum extracts. The

compounds have A, B, C, D tetracyclic skeleton and a side chain, the number of atoms

of the entire carbon skeleton is 30 [102]. Depending on the terminal substituent of the

side chains, the Ganoderma triterpenes are often divided into two classes, Ganoderic

acid (A, B, C, D) and Ganoderol, whose side chain terminals are carboxyl group and

alcoholic hydroxyl group, respectively [103]. Currently, the extraction methods are

ethanol extraction, microwave extraction, ultrasonic extraction and so on [81]. Li et al.

found that the triterpenoids extracted from the broken spores with ethanol could

regulate the expression of key genes and proteins, leading to cell cycle arrest in G0/G1

phase, inducing cell apoptosis, down-regulating MMP-1 and MMP-2, up-regulating the

expression of E-cadherin, resulting into the inhibition of the migration and proliferation

of HCT116 cells and thus had a therapeutic efficacy on colon cancer [104]. Ganoderma

triterpenoids extracted from G. lucidum fruiting bodies by ethanol under reflux can

protect the liver by their antioxidative and radical scavenging activities as well as

inhibition of cell apoptosis [105]. Liu et al. found that triterpenoids extracted from G.

lucidum might be useful components for the treatment of benign prostatic hyperplasia

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through the inhibition of the 5a-reductase [106]. It is also reported that triterpenes can

protect H2O2-injured HepG2 cells by detecting the levels of AST and ALT [103]. Other

pharmacological effects of triterpenes include antiviral [107], anti-osteoclastic

differentiation activities, anti-inflammatory effects, etc [108, 109].

2.3.3. Proteins and peptides

LZ-8 is a polypeptide consisting of 110 amino acid residues with an acetylated amino

terminus and has a molecular mass of 12 kDa, isolated from G. lucidum [110]. Studies

have shown that LZ-8 activates macrophages as well as T lymphocytes, indicating its

ability to activate the innate adaptive immune system in mice [111]. GMI is an

immunomodulatory protein cloned from Ganoderma microsporum. Hsin et al found

that GMI could significantly enhance the cisplatin-mediated cancer cell death

via autophagy. The combination of cisplatin and GMI significantly increased the

cytotoxic effect [112]. In lightproof soybean oil and lard systems, G. lucidum peptide

showed obvious antioxidant, metal chelating and free radical scavenging activities,

indicating its excellent antioxidant capacity. Ganodermin, a 15-KD protein, was

isolated from fruiting bodies of G. lucidum, suggesting that ganodermin inhibited the

mycelial growth of Botrytis cinereal, Fusarium oxysporum and Physalospora piricola

with an IC 50 value (50% inhibitory concentration) of 15.2 mM, 12.4 mM and 18.1

mM, accounting for its antifungal properties [113].

2.3.4. Other compounds

Other compounds extracted from G. lucidum have also been investigated. The

nucleic acids in G. lucidum were discovered and showed that adenine, adenosine, uracil

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and uridine, extracted from the mycelium of the G. capens, demonstrated good

therapeutic effects on progressive malnutrition and myotonic dystrophy [114]. The

methanol extracts of G. lucidum fruiting bodies were purified to obtain six types of

sterols, fungi sterol, 5,6-dihydroergosterol, ergosterol, ergosterol peroxide, 9(11)-

dehydroergosterol peroxide, and demethylincisterol A3. Among them, fungi sterol,

9(11)-dehydroergosterol peroxide and demethylincisterol A3 were reported to possess

strong inhibitory properties on EBV-EA (Epstein–Barr virus early antigen) [115]. Three

sterols named 5a-ergost-7-en-3b-ol, 5a-ergosta-7,22-dien-3b-ol and 5,8-epidioxy-

5a,8a-ergosta-6,22-dien-3b-ol were extracted from G. annulare, with certain antifungal

activity [116]. Other sterols extracted from G. lucidum contain 22E,24R-ergosta-7,22-

diene-3β,5α,6β,9α,14α-pentol, 22E,24R-ergosta-7, 22-diene-3β,5α, 6β-triol, 22E, 24R-

ergosta-7, 22-diene-3β, 5α,6β,9α-tetraol, 3β, 5α-dihydroxy-(22E,24R)-ergosta-7, 22-

diene-6-one and 3β,5α, 9α-trihydroxy-(22E,24R)-ergosta-7,22-diene-6-one [117].

2.4. Ganoderma pharmaceutical dosage form

At present, there are four main approaches for the use of Ganoderma within the

research and development of health products and pharmaceuticals: using fruit bodies as

raw materials; using mycelia or fermentation broth produced by liquid deep

fermentation as raw materials; using solid fermentation broth as raw materials; using

broken or unbroken spores as raw materials [118].

2.4.1. Capsules

Capsules have the advantage of facilitating the use of drugs to mask bad odors and

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delay the deterioration of drugs [119]. Microcrystalline cellulose acts as an absorbent

and filler, PEG 6000 acts as a binder, and 50% ethanol acts as a wetting agent. As an

example, polyethylene glycol 6000 was dissolved in 50% ethanol at a concentration of

about 35% and made into a soft material. It was granulated through a 20-mesh screen

and dried at 60 °C. Then the capsules were filled with a 20-60 mesh sieve and

magnesium stearate was added. Capsules containing ganoderma components can

significantly enhance mitogen-induced lymphoproliferative responses in

immunocompromised cancer children [120].

2.4.2. Oral Liquid

Oral solutions have the advantages of small dosage (less than 10 ml), rapid

absorption, convenience of carrying around and administering, and easy storage [121].

In an example, Ganoderma powder was leached in boiling water for 1 h and was

subsequently added to a certain amount of water and filtered with a 40 μm aperture

filter. The filter residue was repeatedly leached and filtered, and the leach liquor

obtained was combined. The refractometer was used to determine the content of soluble

solids. Based on the use of 1.5% of excipients and 2.0% of sugar, the lucid Ganoderma

extract was made into oral liquid, and the flavor was evaluated organoleptically.

Extraction rate equals to the proportion of polysaccharide content to G. lucidum powder

weight [122]. Ganoderma oral liquid significantly improved learning and memory in a

sleep deprived rat model [123].

2.4.3. Chewable tablets

Preparation method and production process of GLS powder for chewable tablets:

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Firstly, calcium hydrogen phosphate, sucrose and the main active component are mixed

thoroughly prior to sieving. Then the mixture was sifted and prepared to produce soft

materials with 40% syrup followed by granule screening. The prescribed amount of

magnesium stearate (5 mg/1g of mixture) was added to the dried granules and mixed,

and the content was tested and tableted. Through the inspection of the influencing

factors of the prescription (light, high temperature) and production optimization, G.

lucidum powdered chewing tablets with easy operation, mature technology, and good

stability were obtained [124].

2.4.4. Rice Wine

The boiled non-glutinous rice was cooled, and mixed with koji, flour and

saccharomyces cerevisiae before incubating at 25 °C for 2 days. Typically, 50 g of

cooled glutinous rice and 50 g of non-glutinous rice were added to the mixture as well

as the powder of G. lucidum fruiting body. After the mixture was fermented at 25 °C

for 10 days, it was centrifuged to obtain yakju. GL-1 yakju brewed by adding 0.1% G.

lucidum mixture showed the best acceptability. It is a new type of functional rice wine

with anti-hypertensive properties [125].

2.4.5. Compound Beverage with Ganoderma Lucidum and Black Tea

Dried G. lucidum was crushed by a grinder and sieved through an 80 mesh (80 mesh

holes per inch of meshscreen, each of which has a diameter size of 0.18 mm) to prepare

dry G. lucidum powder. The dried powder was poured into 40 times its volume of water,

followed by adding 1% cellulase and 3% pectinase. The mixture was leached at a

constant temperature of 50 °C for 1 h, and the supernatant was collected to obtain a G.

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lucidum enzymatic hydrolysate. Black tea leach liquor was prepared according to the

ratio of material to water of 2.5:100 and bathed at 80 °C for 25 minutes. G. lucidum

enzymatic hydrolysate and black tea extract and water were mixed into a solution at the

ratio of 40:40:20. Finally, 3% β-cyclodextrin, 0.5% maltodextrin, 0.5% sugar, 0.015%

sodium D-isoascorbate, 0.05% CMC-Na and 0.05% sodium alginate were formulated

into the compound beverage of G. lucidum and black tea [126].

3. Pharmacological effects of Ganoderma and its extracts on neurological diseases

As a medicine for the treatment of AD, PD, CVD and other neurological diseases,

Ganoderma has received more and more attention. Fig. 6 shows that the following

content of this article aims to fully summarize and discuss the efficacy and mechanism

of Ganoderma and its extracts such as triterpenes, polysaccharide and acid on the

protection of neurological diseases.

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Fig. 6. The neuroprotection of Ganoderma and its extracts.

3.1. Abnormal Neurogenesis

Niche is defined as a micro environment anatomically maintaining stem cells and

functionally controlling their development in brain [127]. It provides the environment

for the first level of signal integration. In the adult brain, niche is divided into two

regions--sub-granular zone in the dentate gyrus of the hippocampus, and the

subventricular zone of the lateral ventricles. Fig. 7A shows the process of neurogenesis

in adult sub-granular zone and Fig. 7B shows the cell types. Activated neural stem cells

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produce progenitor cells, which in turn give rise to neuroblasts and sequence migrate

to the granular layer to differentiate into dentate-gyrus granule cells. Newborn neurons

develop dendrites and axons and integrate into existing neural circuits [128]. Different

types of neural cells express specific proteins at different stages of development. BrdU

is a thymine derivative that can be inserted into newly synthesized DNA in proliferating

cells instead of thymine during cell division, making this nucleoside analog an excellent

marker of cell cycle and proliferation [129].

Fig. 7. (A) 5 stages of neurogenesis in sub-granular zone area. (B) Cell types involved

in neurogenesis in sub-granular zone [130]. (C) Summarizing the Ganoderma effects

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on neurogenesis.

Based on the close relationship between neurogenesis and various diseases, it is a

promising method to treat certain disorders by regulating the process of neurogenesis

[131]. Polysaccharide is a chemical compound extracted from G. lucidum (GLP). After

oral gavage for 90 days with GLP, APP/PS1 mice treated with GLP spent less time to

reach the position of the platform but spent more time in locating the hidden platform

compared with vehicle-treated mice, suggesting that prolonged GLP exposure may

improve spatial-memory impairment [132]. In dentate gyrus, the number of

BrdU/NeuN double-positive cells was markedly increased with no significant change

in the proportion of double-positive cells in the BrdU retaining cells, manifesting that

GLP enhances neurogenesis with no affection on neuronal lineage commitment [133].

The number of Ki67 and SOX2 double-positive cells was increased with no change in

the number of SOX2 positive cells indicating that GLP promote progenitor cells

proliferation but did not affect NPC pool in APP/PS1 mice [134].

Several chemical constituents were extracted from the fruiting bodies of Ganoderma

named as spirolingzhines A-D, four meroterpenoids with a spiro motif, lingzhines A–F,

six meroterpenoids with diverse ring systems, along with ganomycin I and 4-(2,5-

dihydroxyphenyl)-4-oxobutanoic acid [135]. Research has shown that except for

lingzhine C and ganomycin I (11), which inhibited neural stem cells (neural stem cell)

proliferation compared with a DMSO control, these chemical components promote

neural stem cell proliferation, detected by neurosphere clonal and BrdU incorporation

assays in vitro [136].

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An incision in the dorsal skin along the median, followed by exposure of the thoracic

segment of the spinal cord under a dissecting microscope, and then the right transection

of the spinal cord can be performed. Two weeks after SCI (spinal cord injury), there

were more BrdU positive cells in the ependymal membrane of the group treated with

GLS solution than those without administration [137]. Moreover, BrdU-positive cells

in the tube of the central canal of the spinal cord of the treated group were more than

those of the untreated group. Four weeks after SCI, only a small amount of BrdU

positive cells were found in the ependymal membrane, which was still higher than that

in the untreated group. The result indicates that GLS solution can promote cell

proliferation in the ependymal tube of the injured central nervous system [138].

Lingzhi-8 extracted from G. lucidum was a mitogen-like protein, which can promote

mitosis and cell growth. Ethanol extracts from G. lucidum showed the best effect on

cell growth acceleration. At higher concentration, ethanol remaining in the extract

during fractionation could be harmful and toxic to cells. However, at low concentration,

growth stimulation elements in such extract could not enhance the proliferation

efficiently. Thus, the optimal concentration of the extract from G. lucidum is 500 μg/ml

[139].

The above results showed that G. lucidum and its extracts could promote the

proliferation of neural stem cells and differentiation of progenitor cells, increase the

number of immature neurons, increase the mature neurons with transmission function

and improve the learning and memory ability of mice. However, neurogenesis is not a

mere recording of the final result, but a dynamic developmental process which needs

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to be completely monitored, that is, brain sections should be stained and analyzed at

different time points throughout the whole experiment (Fig. 7C).

3.2. Alzheimer’s Disease (AD)

According to ADI (Alzheimer's Disease International) data from 2016, there were

about 46.8 million cases of dementia in 2015 with an annual increase in incidence of

about 7.70 million, that is, one person will be diagnosed with AD every 4 second [140].

The number of global dementia cases has doubled in the last 20 years, and is predicted

to reach 75.6 million in 2030 and 135 million in 2050 [141]. AD is the main cause of

dementia in developing countries [142]. There is very little chance of getting proper

health care for people with dementia, even in the case of most high-income countries,

only about 50% of people with dementia get diagnosed. In low- and middle-income

countries, less than 10% of cases are diagnosed [143].

From a genetic point of view, AD is a heterogeneous disease which can be divided

into Familial AD (FAD) and Sporadic AD (SAD). Researchers have identified several

potential pathogenic mechanisms of AD including β-amyloid (Aβ) aggregation and

deposition followed by plaque development [144]. tau hyperphosphorylation followed

by neurofibrillary tangles formation [145]. inflammatory processes [146]. oxidative

stress [147]. neurovascular dysfunction [148]. mitochondrial dysfunction [149],

transmitter deficits [150] and so on.

GLP were extracted from the dried conidial powder of G. lucidum, defatted with 95%

EtOH followed by 5 h extraction with boiling water. Research found that pre-treatment

of BV2 cells with GLP followed by LPS (lipopolysaccharide, a substance which

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induces an inflammatory response in the central nervous system) stimulation could

inhibit LPS-induced proinflammatory cytokines IL-1β, IL-6 and inducible nitric oxide

synthase (iNOS) expressions, and also up-regulated the anti-inflammatory cytokine

TGFβ expression [151]. The morphological modulations associated with the LPS

stimulation were inhibited by GLP pre-treatment such as cell area, perimeter, Feret’s

diameter and circularity. Pre-treatment with GLP (1 and 0.1 μg/ml for BV2 and primary

microglia, respectively) significantly reduced the phagocytosis events [59]. Fig. 8

depicts the potential signaling pathways under these experimental results.

Fig. 8. Scheme summarizing the proposed IL-1β and iNOS signaling mechanisms

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underlying neuroprotection of G. lucidum polysaccharides (GLP) against Alzheimer’s

disease.

Results of the study showed that G. lucidum extract, derived from dried fruiting

bodies of G. lucidum with ethanol, significantly increased PDH (pyruvate

dehydrogenase) [152], α-KGDH (α-ketoglutarate dehydrogenase) [153], SDH

(Succinate dehydrogense) [154], complexes I and II activities compared to controls

[155]. The levels of lipid peroxidation in the G. lucidum-treated group were

significantly lower than those in the control group. However, there was no statistically

significant difference in the enzyme activities between the two groups. The activity of

G. lucidum extract was considered to result from its antioxidant activity. In general,

these results showed that G. lucidum extract might effectively improve brain

mitochondrial function in aged rats, suggesting its potential anti-neurodegenerative-

diseases qualities as well as prospective application in the future [156].

D-galactose (D-gal) is a reducing sugar that is capable of forming advanced glycation

end products in the body, resulting in a simulated degeneration in the aging of the

immune system [157]. PSG-1 was a homogeneous protein-bound polysaccharide,

extracted from the fruiting bodies of G. atrum [158]. Body weights of D-gal-treated

mice followed by PSG-1 administration were increased significantly, compared with

the D-gal group. The increase of MDA (a breakdown product of lipid peroxidation,

generally used as a standard of oxidative stress) contents induced by D-gal in liver,

brain, and spleen was attenuated by PSG-1 administration [159]. Moreover, PSG-1 may

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attenuate oxidative stress by regulating activities of these antioxidant enzymes

including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase

(GPx), which are the first line of protection for tissues or cells against oxidative stress

in the D-gal-treated mice. Administration of PSG-1 also promoted proliferation of

lymphocytes in D-gal-treated mice [160].

The immunoreactivity of synaptophysin is significantly reduced in neuritis of Aβ25-

35-treated neurons, and the distribution of synaptophysin is unevenly distributed [161].

Instead, synaptophysin aggregated to form a stained plaque along the axon [162].

However, synaptophysin was evenly distributed in the control group and the G. lucidum

aqueous extract (GLA)-treated group. Pre-treatment with GLA inhibited the

downregulation of synaptic vesicular protein immunoreactivity induced by Aβ25-35 as

well as preserved the neurite network at high dose. Pre-treatment of GLA significantly

attenuated the Aβ25-35-induced DEVD-cleavage activity, resulting in reducing Aβ25–35

toxicity. GLA reduced the number of apoptotic bodies triggered by Aβ42 peptide [163].

The result suggested a protective effect of GLA on nerve cells against Aβ peptide.

Given the protective effect of G. lucidum and its extracts on Alzheimer's disease

through properties of anti-inflammation, oxidation resistance, reducing Aβ toxicity, it

is expected to become a promisingly clinical therapeutic drug with low side effects.

3.3. Parkinson’s Disease (PD)

Dr. James Parkinson first described the concept, course of disease and characteristic

clinical symptoms of PD in 1817 until Dr. Jean Martin Charcot named it Parkinson's

disease (PD) in 1877, as widely known today [164]. Neostriatum, the major afferent

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structure of the basal ganglia, accepts afferent glutamatergic nerves from a wide area

of the cerebral cortex [165]. The striatum has projecting neurons that express D1

(excitatory) or D2 (inhibitory) dopamine receptors and also include interneurons that

are transmitted by Ach [166]. The nigrostriatal dopaminergic-cholinergic neurological

imbalance theory suggests that two neurotransmitters (DA and Ach) antagonize each

other and are in a state of homeostasis and participate in the regulation of motor function

in a normal state [167].

Currently, drugs used for clinical treatment of PD are divided into pseudo-dopamine

drugs (Dopamine prodrugs-levodopa, Levodopa degradation inhibitor carbidopa,

Monoamine oxidase B inhibitor-selegiline etc.), central cholinergic receptor blockers

(central M receptor blocker-benzhexol) and neuroprotective agents [168]. However,

each drug has its own seriously adverse reactions, especially those requiring long-term

use. Therefore, there is an urgent need to develop a new drug for reversing the

neurological damage caused by PD.

In recent years, studies have shown that neuroinflammation is also involved in the

development of PD. McGeer et al. found that activated microglia and astrocytes were

present around the injured neurons in substantia nigra pars compacta of PD patients

[169]. NO, ROS, and pro-inflammatory cytokines were significantly increased in

substantia nigra of PD patients. Pretreatment with high dose of G. lucidum potently

reduced the increase of NO and SOD induced by LPS or cell membrane fractions in a

concentration-dependent manner, significantly decreased the release of TNF-α and IL-

1β after LPS and CF treated with MPP+ (a toxic metabolite of MPTP, causing symptoms

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of PD) [170]. At 400 μg/ml, G. lucidum significantly attenuated MPP+-induced

reduction of [3H] DA uptake, which only decreased by 35% and 38%, respectively in

the absence and presence of microglia co-cultures. Moreover, pretreatment of G.

lucidum also significantly attenuated LPS-induced decrease in [3H] DA uptake [171].

Through primary mesencephalic cultures, GLP could protect dopaminergic neurons

against MPP+ and rotenone at the concentrations of 100, 50 and 25 μg/ml in a dose-

dependent manner [172]. The interesting thing is, even if no toxins were added to cell

culture system, GLP treatment increased the survival rate of tyrosine hydroxylase (TH)

immuno-reactive neurons, as well as the length of neurites of dopaminergic neurons.

TH is the first enzyme that catalyzes tyrosine to form dopamine in vivo and is also the

rate-limiting enzyme [173]. Furthermore, GLP dramatically decreased the apoptotic-

cell number and increased the mitochondrial membrane potential which was declined

by MPP+ and rotenone in a dose-dependent manner. Besides, GLP treatment reduced

the ROS formation induced by MPP+ and rotenone at the concentrations of 100, 50 and

25 μg/ml. Collectively, the results showed that GLP possesses neuroprotective

properties against MPP+ and rotenone neurotoxicity by inhibiting oxidative stress in

primary mesencephalic dopaminergic cell cultures due to its antioxidant activity [174].

Triterpenoids in Ganoderma spore oil content up to 30 percent. The use of GLSoil can

significantly reduce the involuntary tremor of the forelimbs and other actions induced

by MPTP, extend the pole time and also increase the amount of DA and metabolites in

the striatum [175]. The number of TH-positive cells and the TH protein expression were

significantly increased in the Ganoderma spore oil group compared with non-

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medication group [176]. The results of GLSoil on MPTP mouse model in behavioral

changes, neurotransmitter content, pathological damage, etc. are highly suggestive that

GLSoil can effectively alleviate the selective damage to substantia nigra DA neurons

by the strong neurotoxin MPTP, with exact neuroprotective effects [177].

In conclusion, G. lucidum improves Parkinson's-like symptoms in animal models

primarily by combating inflammatory reactions and oxidative stress and protecting

dopaminergic neurons, but the efficiency and intensity of this indirect mechanism are

limited, so whether or not G. lucidum can promote neuronal DA secretion, or whether

it can increase the expression of certain molecular changes in DA synthesis step are to

be explored. These findings can provide useful information for the development of

more effective dopamine therapies.

3.4. Cerebrovascular disease (CVD)

CVD is a common and frequently-occurring disease that endangers human health

and life. It is the third leading cause of death following heart disease and cancer.

According to its nature, CVD can be divided into ischemic and hemorrhagic CVD.

Among them, ischemic stroke is more common in clinical CVD, the number of patients

accounts for 83% of all CVD patients [178]. Currently, drug treatment of ischemic

stroke focuses on thrombolytic therapy and neuroprotection. The former aims to

eliminate thrombus blockage, the latter purpose is to interfere with the ischemic cascade,

to prevent secondary damage and to protect the ischemic penumbra of neuronal damage.

Currently, they can be more refined into anti-platelet aggregation drugs [179],

anticoagulants [180], thrombolytic drugs [181], brain protectants, neuro-protective

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agents [182], vasodilators [183] and inflammatory response inhibitors.

Cerebral ischemia-reperfusion injury is a phenomenon in ischemic CVD, manifested

as cerebral ischemia, lasting for a certain period of time and then restoring blood

perfusion, adversely giving rise to more serious brain dysfunctions. Reperfusion injury

involves a variety of mechanisms, including oxidative stress [184], inflammatory

damage [185] and excitotoxicity. Among them, oxidative stress plays an important role

in I/R injury and has become one of the hot topics in this field.

Ganoderma total sterol (GS) increased neuronal viability after

hypoxia/reoxygenation (H/R) and also significantly reduced the malondialdehyde

content and ROS production, increased the activity of manganese superoxide dismutase

and blocked the translocation of nuclear factor kappa B and H/R-induced interleukin-

1h and Tumor Necrosis Factor alpha (TNF-α, a proinflammatory cytokine mainly

produced by macrophages and monocytes) production [186]. These findings suggested

that GS might help treat H/R-induced oxidative stress and inflammatory responses.

Furthermore, since pretreatment with GS1 significantly attenuated the decline of

neuronal activity and the formation of ROS, and that GS1 had a stronger protective

effect on neurons than GS at the same dose in the neuroprotective effect of GS on H/R

[187].

In the model of I/R, results showed that pretreatment with GLA for 3 days and 7 days

reduced the loss of neurons in the hippocampus, decreased the contents of

malondialdehyde in the hippocampus and serum, and decreased the levels of TNF-α

and IL-8 levels. It also increased SOD activity in the hippocampus and serum,

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indicating that pretreatment with GLA has a protective effect on cerebral I/R injury

through its antioxidant and anti-inflammatory effects [188].

Pretreatment with G. lucidum mycelia (MAK) for one week significantly reduced

H/I-induced neurological deficits and infarct volume. In vitro chemical analysis showed

that MAK significantly inhibited superoxide production, neuronal cell death and

vacuolization in the ischemic penumbra, with a decrease in the number of TUNEL

(TdT-mediated dUTP Nick-End Labeling: Terminal Deoxynucleotidyl Transferase

(TdT) acts as a catalyst to attach fluorescein-dUTP to the exposed 3'-OH at the time of

cleavage of genomic DNA due to apoptosis or injury, so that apoptotic cells can be

observed under a fluorescence microscope or detected by flow cytometry) or cleaved

caspase-3 positive cells [189]. In addition, MAK decreases the expression of receptor-

interacting protein kinase 3 mRNA and protein expression. These results indicated that

MAK conferred resistance to apoptosis and necrotic cell death in type 2 diabetic mice

and reduces cerebral ischemic injury induced by H/I [190].

3.5. Epilepsy

Epilepsy is one of the most common widespread non-communicable diseases of the

nervous system in the world and is estimated to affect about 70 million people, of whom

up to 90% live in low- and middle-income countries [191]. Epilepsy is a sudden,

abnormal discharge of neurons in the brain, a chronic condition that causes transient

brain dysfunction. Epilepsy and many forms of acquired encephalopathy are

concomitant (such as cancer, infection, stroke, and traumatic brain injury) [192]. The

pathological mechanism of epilepsy can be divided into neurotransmitter abnormalities

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[193], ion channel dysfunction [194], glial dysfunction [195], immune and

inflammatory factors [196] and molecular genetic mechanism [197].

According to study by Wang et al., at the ninth day of culturing, the nutrient

maintaining medium was replaced with extracellular medium without Mg2+ for 3 h. The

extracellular fluid containing no magnesium ions significantly increased the amount of

calcium in the cytoplasm of neurons. The concentration of calcium reached a peak at

about 30 seconds. However, when GLP was added to Mg2+-containing extracellular

fluid, Ca2+ fluorescence intensity in hippocampal neurons was significantly reduced.

This indicates that GLP can inhibit Ca2+ accumulation in neuronal cytoplasm caused by

Mg2+-free medium. Moreover, GLP treatment can increase CaMKIIα expression in

epileptic hippocampal neurons protecting epileptic neurons [198]. N-Cadherin is a

member of the cadherin family, which plays an important role in targeting the growth

of axons and the construction of correct synaptic connections [199]. Abnormal

expression of N-cadherin leads to neurodevelopmental disorders (such as schizophrenia

and epilepsy) and behavioral defects in animal models [200]. The results showed that

after GLS treatment, the number of normal hippocampal neurons increased and the

morphology was preserved well. In addition, neurotrophin-4 expression was

significantly increased while N-cadherin expression was decreased in the GLS-treated

group as compared to the model group, suggesting that GLS protected hippocampal

neurons by promoting the expression of neurotrophin-4 and inhibiting N-cadherin

expression [201].

Both Neural Cell Adhesion Molecule (NCAM-1) and NCAM-L1 participate in the

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occurrence and development of epilepsy induced by pentylenetetrazol [202]. By down-

regulating the expression of NCAM-1 and NCAM-L1, GLS powder can inhibit the

growth of axons and the transmembrane signal transduction of the nervous system,

reduce cell adhesion, decrease synaptic plasticity of the nervous system and have anti-

epileptic effects. The results indicate that GLS powder has clinical potential as a drug

for protecting the brain from epilepsy [203].

3.6. Spinal cord injury (SCI)

SCI is a central nervous system disorder that causes major changes in spinal cord

dysfunction or loss due to direct or indirect spinal cord injury [204]. Acute SCI is

caused by direct or indirect external causes of spinal cord injury, damage in the

corresponding segments of a variety of sports, sensory and sphincter dysfunction,

abnormal muscle tone and pathological reflex changes [205].

The spinal cord trauma model was created by the occlusion of the spinal cord with

an aneurysm clip [206]. After traumatic SCI, caspase-3 activity, TNF-α levels,

myeloperoxidase activity, malondialdehyde (MDA) levels, and nitric oxide (NO) levels

were markedly increased using G. lucidum [207]. However, GLP significantly reduce

the expression of these factors. Moreover, the number of normal motor neurons in the

GLP group was significantly higher than that in the trauma group. The results suggest

that GLP has a beneficial effect on the protection of normal spinal cord morphology,

ultrastructure and function by inhibiting apoptosis, reducing inflammatory response and

oxidative stress [206].

3.7. Neural tube defects (NTDs)

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NTDs are serious birth defects in the central nervous system that originate during

embryonic development when the neural tube is not completely closed, including spina

bifida and anencephaly. G. lucidum spore (GLS) was fed to the pregnant mice twice a

day from embryo embryonic day 0 to embryonic day 10.5. At embryonic day 7.75, all-

trans retinoic acid was given to the pregnant mice for single time and embryos were

sampled from pregnant mice at embryonic day 10.5 [208]. According to embryo

morphological observation, the stillbirth of pregnant rats in the model group was

significantly increased, showing various forms of NTDs (e.g. no brain, cerebral oal,

etc.), facial morphology abnormalities, short tail or no tail. However, most of the

embryo morphology was normal except for a very small number of embryos showing

NTDs in the GLS group. At the same time, there were also statistical differences in

crown-rump length between the two groups. In addition, the number of neuroepithelial

cells expressing nestin in embryonic neural tube of the administration group was

significantly higher than that of the model group, and the distribution was more

extensive. GLS could significantly attenuate all-trans retinoic acid-induced reduction

of cyclin-dependent protein kinase 2 (Cdk2) and cyclin-dependent protein kinase 4

(Cdk4 and Cdk2 are key molecules that allow cells to pass the G1 phase normally) [209]

transcription, making DNA replication enters S phase through G1 phase, allowing more

cells to undergo normal division and proliferation, so as to meet the needs of embryonic

development. These results showed that GLSs reduced the incidence of NTDs in

pregnant mice induced by retinoic acid [210].

3.8. Neurasthenia

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Neurasthenia is a Brain dysfunction syndrome characterized by sleep disorders due

to persistent long-term nervousness in the brain, which leads to brain excitement and

dysfunction of inhibition. Patients with neurasthenia have more stressful life, lower

self-regulation ability, lower interpersonal harmony and worse sleep status compared

with healthy people.

The 132 neurasthenic patients enrolled in this study were randomized to a placebo

group and a GLP-treatment group. The GLP and placebo formulations were filled in

the same capsule to create a double-blind trial. After eight weeks of treatment, the

severity of Clinical Global Impression (CGI) and the fatigue index in the GLP group

were significantly lower than those in the placebo group (15.5% and 28.3% versus 4.9%

and 20.1%), but the happiness was significantly improved (38.7% versus 29.7%),

indicating a good therapeutic effect on neurasthenia of GLP with a promising

application prospect [26]. This effect may come from the protection of the limbic

nervous system by G. lucidum, extensive regulation of immunity, inhibition of

spontaneous activity, and relaxation of skeletal muscle. Through the record of animal

model electroencephalogram and electromyogram, it was found that the aqueous

extract of G. lucidum had no effect on the sleep structure of normal rats, no matter in

high dose or low dose. However, in pentobarbital-treated rats, the aqueous extract of G.

lucidum significantly induced rats to enter deep sleep, reduced the tendency for arousal,

decreased non-REM (rapid eye movement) sleep time and light sleep time. Under the

action of the aqueous extract of G. lucidum, the locomotor activity of normal mice was

inhibited. Flumazenil, a benzodiazepine receptor antagonist, can antagonize the above

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pharmacological effects, suggesting that the aqueous extract of G. lucidum may be an

herb at least partially with benzodiazepine-like hypnotic activity [211].

3.9. Depression

Depression is a type of mood disorder characterized by significant and prolonged

mood depressions, slow thinking, impaired cognitive function, diminished will activity

and somatic symptoms as the main clinical features.

Water-soluble extracts prepared from the MAK contain a variety of nutrients

including polysaccharides, triterpenes, β-glucans and lignin [22]. Compared with the

control group, rats received oral administration of MAK had a shorter immobility time

in the forced swimming test (FST), but in the open-field test (OFT), there was no

significant change in the locomotor activity of the animals, indicating that the MAK

relieved depression, and this effect was completely different from psychostimulants like

amphetamine and caffeine [212]. The number of head twitches caused by DOI ((±)-1-

(2,5-dimethoxy-4-iodo-phenyl)-2-aminopropane hydrochloride, is believed that

induces head twitches through direct agonism of the 5-HT2A receptor) was significantly

reduced upon MAK administration without changing head twitches induced by 5-

hydroxy-L-tryp-tophan, the precursor of 5-HT which increases the concentration of 5-

HT in synaptic clefts. These results indicated that MAK’s antidepressant mechanism is

agonism of 5-HT2A receptor rather than 5-HT reuptake inhibition [213]. Similarly,

according to studies, ethanol extract of G. lucidum also has anti-depressant activity

similar to fluoxetine. Compared with vehicle control, G. lucidum significantly reduced

immobility in FST and Tail suspension test (TST), suggesting that G. lucidum has

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antidepressant potential, and the most significant dose is 130 mg/kg [214]. In a clinical

trial, 48 breast cancer patients treated with endocrine therapy were divided into control

group and group administrated by GLSs. After 4 weeks of treatment, the Cancer-related

fatigue (CRF) index was calculated to prove that GLSs can significantly reduce CRF,

and have a good effect on the depression, which is related to immune-modulating action

[215].

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Neurological

Diseases

Therapeutic

Components

Mechanism Ref.

Neurogenesis

GLP Promoted progenitor cells proliferation [134]

Lingzhines A–F Promoted neural stem cells proliferation [136]

Spore solution Promoted cell proliferation [138]

Lingzhi-8 Promoted mitosis and cell growth [139]

AD

GLP

Inhibited the expressions of IL-1β, IL-6 and (iNOS).

Upregulated the expression of TGFβ.

[59]

Fruiting body ethanol

extract

Increased PDH, α-KGDH, SDH, complexes I and II, reduce

lipid peroxidation

[2]

PSG-1

Reduced MDA, regulate SOD, CAT, and GPx, promoted

proliferation of lymphocyte

[160]

GLA

Inhibited the downregulation of synaptic vesicular protein

immuno-reactivity, preserve the neurite network/ morphology

of neurons, attenuated DEVD-cleavage

[163]

PD

Polysaccharides and

ergosterin

Reduced NO and SOD, decrease release of TNF-α and IL-1β,

increase [3H] DA uptake

[171]

GLP

Increased the survival rate of THir neurons/ the length of

neurites of dopaminergic neurons, increased the

[134]

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mitochondrial membrane potential, reduced the ROS

Triterpenoids

Improved PD mice behavior, increase TH protein expression/

TH-positive cells

[177]

CVD

GLP

reduced infarct size/ neurological deficits/ neuronal

apoptosis/ cell death/damage/ caspase-3, -8, -9 and Bax, Bcl-

2 expression

[216]

GS

Reduced the malondialdehyde/ROS/ IL-1h/ TNF-α/ ROS,

increase the activity of manganese superoxide dismutase

[187]

GLA

Decreased the contents of malondialdehyde/ TNF-α/ IL-8,

increased SOD activity

[217]

Mycelia (MAK)

Inhibited neurological deficits/ superoxide production/

neuronal cell death/vacuolization/ number of TUNEL- or

cleaved caspase-3 positive cells

[190]

Epilepsy

GLP Inhibited Ca2+ accumulation, increase CaMKIIα expression [198]

GLS

Preserved the number of normal hippocampal neurons/

morphology, increase neurotrophin-4, decrease N-cadherin

expression

[201]

Spore powder

Down-regulated the expression of NCAM-1 and NCAM-L1,

reduced cell adhesion, decreased synaptic plasticity

[203]

SCI GLP

Reduced caspase-3 /TNF-α/ myeloperoxidase activity/

MDA/ NO levels. Increased normal motor neurons.

[206]

NTD Spores Reduced abnormal embryo morphology, increase nestin [210]

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Table 1. The summary for active ingredients of Ganoderma and mechanisms of

neuroprotection.

4. Combination of G. lucidum and western medicines for clinical treatment of

neurological diseases

The fundamental difference between TCM and Western medicine lies in the fact that

TCM takes a holistic approach, putting people in the center, and focusing on the laws

of our functional state, movement state, and state changes to grasp and regulate human

life activities [218]. Therefore, the combined application of TCM and western medicine

expression/ Cdk2 and Cdk4 transcription

Neurasthenia

GLP

Clinically, VASwb was reduced of patients with depression,

increase VAS and CGI, improve patients' happiness and

alleviate depressed mood.

[26]

the aqueous extract

of G. lucidum

Significantly reduced sleep latency, increased sleep time,

non-REM sleep time and mild sleep time in pentobarbital-

treated rats

[211]

Depression

MAK

Reduced immobility time in FST with no significant changes

in OFT, agonists of 5-HT2A receptor.

[213]

Ethanol extract reduced immobility in FST and TST, similar to fluoxetine [214]

Spores

Clinically improved CRF indexes (FACT-F, HADS, EORTC,

QLQ-C30), attenuated CRF, as well as immune-modulating

action

[215]

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can complement each other, and the pathological mechanism of the disease can be

analyzed and the dosing plan can be formulated from the perspective of overall and

decomposition [219].

As a substance of TCM, Ganoderma possesses properties like other TCM substances

including low cost, wide potency, enhanced tolerance, low resistance and the like [220].

Side effects refer to pharmacological effects other than the therapeutic purpose that

occur after the application of a therapeutic amount of a drug. Compared with Western

medicine, TCM has fewer side effects and is more likely to decline after withdrawal

[221]. In the meantime, TCM also possess disadvantages like administration methods

and dosing regimens are difficult to standardize, slow efficacy which makes it require

long-term use. Similarly, western medicine for the treatment of neurological diseases

generally has strengths and weaknesses as well. Although western medicine has quick

effect and strong specificity, it has a large side effect and poor tolerance [222]. It is easy

to cause other complications and is harmful to the patient's recovery after illness. There

are many reports about the treatment of neurological diseases with combination of TCM

and western medicine in the laboratory as well as in clinical practice [223].

Long-term hyperglycemia caused by diabetes, resulting in metabolic disorders,

neurotrophic factor loss and microvascular disease, thus gives rise to diabetic peripheral

neuropathy. Polyjuice potion composed of Angelica, Codonopsis, Radix Paeoniae Alba,

Rhizoma Chuanxiong, Millettia, Dilong Gan, Astragalus and other TCM plays a role in

promoting blood circulation, dredging collaterals. The results showed that the total

effective rate of treatment, motor nerve conduction velocity, sensory nerve conduction

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velocity and SOD levels of experimental group patients were higher than that of control

group, indicating a better treatment effect [224].

Although there are few reports on the joint application of Ganoderma and western

medicine at present, the research direction is of great value. As a representative of TCM,

Ganoderma also has a wide range of effects, high tolerance, gentle side effects and

other advantages. In view of the inhibiting effects of inflammatory cytokines and

upregulation of anti-inflammatory cytokines by GLP extracted, the combination of GLP

with AChE inhibitors such as galanthamine and huperzine may allow the co-treatment

of symptoms of AD patients from two levels, as well as play a role in reducing the

dosage of AChE inhibitors and its side effects, such as nausea, vomiting, diarrhea and

so on. G. lucidum as a neuroprotective agent can well protect dopamine neurons and

increase dopamine uptake, combined with DA prodrugs levodopa and levodopa

degradation inhibitor carbidopa may enhance the control over the course of the PD,

reduce the dosage of western medicines and prolong the decay time of western

medicines. Currently, treatment protocols for acute cerebral ischemia are divided into

thrombolysis and neuroprotection. Preventing the cascade reaction caused by hypoxia

and rescuing cells in penumbra zone is very necessary to relieve the symptoms of

patients with cerebral ischemia, improve the quality of life and reduce the risk of

complications. Due to the anti-oxidant and anti-inflammatory ability of G. lucidum and

its inhibitory effects on apoptosis induced by hypoxia, the combined use of G. lucidum

and thrombolytic drug urokinase may reduce the ischemic area of stroke patients and

protect the ischemic core or surrounding cells, inhibit the inflammatory response,

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promote the rehabilitation of neurological function after stroke and improve the

prognosis. Combined with Phenobarbital, which inhibits the discharge of the lesion,

GLP can reduce the dosage of Phenobarbital, reduce the risk of Phenobarbital addiction,

and make the brain return to the normal discharge level. GLP possesses anti-apoptosis,

anti-inflammation and oxidative stress, so as to maintain the normal morphology of

spinal cord. GLP possesses anti-apoptosis, anti-inflammation and oxidative stress

properties, maintaining the normal morphology of spinal cord tissue. Taking GLP

regularly as a health product, combined with the steroid drug Methylprednisolone after

accidental SCI, may relieve the symptoms and reduce the amount of

Methylprednisolone used and thus reducing the side effects caused by

Methylprednisolone. Moreover, it is reported that G. lucidum also has some degree of

therapeutic effect on gastric ulcer [225], so it can reduce side effects caused by steroid

drugs such as gastric ulcer. GLSs can promote the expression of Cdk2 and Cdk4,

thereby maintain the normal cell lineage, so that more cells differentiate and proliferate

to meet the needs of embryonic development. Expectant mothers take a dose of GLP

while taking folic acid during pregnancy, may help fetal spinal cord tissue healthy and

smooth develop and reduce the incidence of NTD.

5. Discussion

For Ganoderma research, different professional articles lack of fit point. For example,

researchers specialized in analysis of chemical composition of Ganoderma will ignore

the pharmacological effects, researchers majored in pharmacological mechanism often

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ignore the structure and chemical formula of which takes part in neuroprotection. Some

studies on Ganoderma still focus on the level of efficacy without a deeper study and

elaboration on the mechanism. Taking AD as an example, the pathogenesis of AD is

very complicated. In the AD mouse model, judging whether or not the cognitive ability

of mice is improved is very incomplete and not objective depending on the influence

of G. lucidum on one of the pathogenesis of AD. It is generally believed that nerve fiber

tangling caused by tau phosphorylation is also one of the major pathogenesis of AD,

but there are few reports on whether or not Ganoderma plays a role in this aspect.

G. lucidum active ingredient extraction process is very complicated. To get total

triterpene from G. lucidum, 100 g fruiting body is needed to be ground into powder, the

concentrated extract was dissolved in chloroform after extracted by ethanol, and then

use silica gel column to extract the purification and followed by a series of steps,

ultimately 1.5 g of the total triterpenes can be obtained. It is even harder to purify the

active ingredients from GLSs, which yield very little. Therefore, if the structure of G.

lucidum can be clarified, artificial synthesis of Ganoderma triterpenes, polysaccharides,

acids, polypeptide and other compounds with higher purity will have positive and far-

reaching significance for mass production, price reduction and clinical practice in the

future.

Some of the most advanced experimental techniques should be applied to study the

relationship between Ganoderma and neurogenesis. For example, two-photon

microscopy can observe the whole process of cell lineage from resting glia-like stem

cells to progenitor cells and eventually forming mature nerves in specific region of

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model animals [226].

With artemisinin as an example, most of the traditional methods of preparing TCMs

are boiling, decocting and steaming with a high temperature. But in fact, artemisinin

completely decomposed when the temperature was higher than 60 °C, let alone had any

therapeutic effect on malaria. Tu Youyou extracted artemisinin from Artemisia annua

with 100% cure of artemisinin on malaria using ether, of which the boiling point was

only 34.6 °C [4]. Similarly, due to improper extraction methods, certain precious

chemical components of Ganoderma may not be completely preserved and excavated

by humans. Therefore, the extraction methods of Ganoderma active ingredients need

to continue to be developed and improved by workers.

For efficacy studies, the experimental site should not be limited to the laboratory, the

experimental subject cannot be limited to animal models such as rat or mice either, in

order to conduct a more comprehensive and definite understanding of the

neuroprotective effect and safety of Ganoderma, a large-scale random sample of

clinical experiment is very necessary. For example, after determining the therapeutic

effect of Ganoderma on animal models in the laboratory, a double-blind experiment

should be performed on patients clinically, Ganoderma is made into tablets or capsules

for patients of experimental group as an adjuvant drug while a placebo is given to the

control group. The recovery of two groups of patients should be learned and recorded

in real time within a few weeks of treatment to obtain the most authentic and reliable

data to evaluate the therapeutic effect of Ganoderma on Parkinson's disease.

Although the toxic effects of Ganoderma total triterpenoids have been reported, the

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side effects of other components such as polysaccharides, ganoderic acid, peptides, etc.

is still rarely reported in other systems of the animal's body other than the nervous

system, such as reproductive toxicity, hematologic toxicity, dermal toxicity, and the like.

Ganoderma and its extracts affect neurodegenerative diseases as well as

neuropsychiatric disorders and even neurodevelopmental disorders. Even if a large

amount of research has been conducted in the past two decades, it still needs to elaborate

the molecular and cellular mechanisms of action in more detail. With the increasing

acceptance of TCM, participation in the global health management system will make

more contributions to human health care. This increase in acceptance has also provided

research opportunities for more extensive research on the medical value of Ganoderma.

Over the past decade, we have observed more and more clinical trials of TCM efficacy.

We predict that in the future there will be more high-quality randomized controlled

trials to meet the needs of modern research and development.

Acknowledgements

This work was financially supported by the National Nature Science Foundation of

China (No. 81771960), the Fundamental Research Funds for the Central Universities

(2017QNA5017) and Key Technologies R&D Program of Zhejiang Province

(2015C02035).

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