The Bioactive Compounds in Medicinal Mushrooms have Potential Protective Effects against Neurodegenerative Diseases

Robert B. Beelman, PhD

Center for Plant and Mushroom, Foods for Health, 404 Rodney A. Erickson Food Science Building, University Park, PA 16802, USA; E-mail: rbb6@psu.edu

INTRODUCTION

Neurodegenerative Diseases (NDs) are incurable and debilitating conditions that result in progressive degeneration and/or death of nerve cells. This causes problems with movement (called ataxias), or mental functioning (called dementias), most commonly seen diseases including Alzheimer’s Disease (AD), Parkinson’s Disease (PD), Huntington’s Disease (HD). Currently, there is no effective treatment that can cure NDs, the treatments can only delay the progression of the diseases for a short term. Therefore, the prevention of the NDs occurrence also attracts researchers’ interests. One hypothesis of the pathogenesis of these diseases is proposed as increased free radical generation, and the consequent elevated oxidative stress in neural system.¹ For other types of chronic diseases such as cancer, epidemiological, animal, and in vitro studies show that the consumption of plant source food can potentially reduce the risk of neurodegenerative diseases attributing to the high anti-oxidative capacity of bioactive compounds in these foods. Mushrooms have been recognized as a healthy functional food because of the high protein and low fat content as well as their phytochemical components like vitamin D and polyphenols.^2-4 Mushroom-derived phytochemical components have anti-oxidative effects and have been confirmed to have therapeutic effects on some chronic diseases like cancer. Researchers deduce that the bioactive compounds in medicinal mushrooms can potentially reduce the risk of NDs via similar action principles.

The potential anti-neurodegenerative actions of medicinal mushrooms have been intensively investigated in numerous animal and cell line studies. In addition to the well-studied polysaccharides such as β-glucan, many small molecules are under investigation for the potential health beneficial effects. The mechanistic studies show that bioactive compounds in various medicinal mushrooms can inhibit activities of neurotransmitter enzyme, stimulate neurite growth, or play a role on anti-inflammatory and anti-oxidative activities.⁵ In this review, we summarize the small bioactive molecules in various medicinal mushrooms that potentially carry the function of reducing oxidative stress in neural systems.

BIOACTIVE COMPOUNDS IN MEDICINAL MUSHROOMS POTENTIALLY AGAINST NEURODEGENERATIVE DISEASES

Hericium Eerinaceus

Hericium erinaceus has the common names as Lion’s mane mushrooms or Pom Pom mushrooms, which is also a culinary mushroom in Asian countries. A clinical trial of daily consumption of 2.88 g H. erinaceus fruiting body dry powder for 16 wks has been performed in 30 Japanese men and women at age 50-80 years old who were diagnosed with mild cognitive impairment. The treatment can significantly (p<0.001) improve the cognitive function scale score (mean=27) of the mushroomtreated patients compared to the controls (mean=24) with no adverse effect detected.6 Similar clinical trials have been performed in senior patients (average age is 75 for treatment group and 77.2 for controls) diagnosed with Parkinson’s disease, degenerative orthopedic disease, cerebrovascular disease, etc. Oral administration of 5 g/day H. erinaceus dry powder for 6 months improved 6 out of 7 dementia patients’ perceptual capacities.7>< 0.001) improve the cognitive function scale score (mean=27) of the mushroomtreated patients compared to the controls (mean=24) with no adverse effect detected.⁶ Similar clinical trials have been performed in senior patients (average age is 75 for treatment group and 77.2 for controls) diagnosed with Parkinson’s disease, degenerative orthopedic disease, cerebrovascular disease, etc. Oral administration of 5 g/day H. erinaceus dry powder for 6 months improved 6 out of 7 dementia patients’ perceptual capacities.⁷

Hericenones (A-H) and Erinacines (A-K & P-Q), originating from fruiting bodies and mycelia respectively, are identified as the bioactive compounds that induce Nerve Growth Factor (NGF) synthesis both in vitro and in vivo.^5,7 Dilinoleoylphosphatidylethanolamine (DLPE) from fruiting bodies of H. erinaceum reduces oxidative stress in Endoplasmic Reticulum (ER) of Neuro-2a cells. 100 ng/ml DLPE significantly (p<0.005) reduced cell viability of Neuro-2a cells treated with tunicamycin, demonstrating the protective effects against oxidative stress.8><0.005) reduced cell viability of Neuro-2a cells treated with tunicamycin, demonstrating the protective effects against oxidative stress.⁸

Termitomyces Albuminosus

Termitomyces albuminosus is consumed as edible mushrooms in many Asian countries such as China, Japan, Singapore as well as South American countries like Chile. This mushroom is also called Termite mushrooms or “Ji Zong” mushrooms in Chinese. Cerebrosides named termitomycesphins A, B, C, D, G, and H have been extracted and identified from dried fruiting bodies of T.albuminosus. The treatment of 10 µg/ ml termitomycesphins A-D for 6 d and 1 µM G and H for 48 hrs increase rat pheochromocytoma PC12 cell neurite outgrowth by 20% and 20-50%, respectively.^9-10 Five fatty acid amides termitomycamide A, B, C, D, and E have been isolated from the same mushrooms. The treatment of 0.1 µg/ml termitomycamide B and E can significantly (p<0.01) reduced ER stress-induced Neuro2a cell death by 20%.11 The animal and human studies of this mushroom against neurodegenerative diseases are lacking. >< 0.01) reduced ER stress-induced Neuro2a cell death by 20%.¹¹ The animal and human studies of this mushroom against neurodegenerative diseases are lacking.

Ganoderma Lucidum

Ganoderma lucidum is a widely used medicinal mushroom in Asian countries with the common name “Ling Zhi” in Chinese. It has been traditionally used to treat many chronic diseases such as cancer, diabetes, hypotension, insomnia, etc. There are numerous bioactive compounds that have been found in G. lucidum, including triterpinoids, nucleotides, sterols, steroids, fatty acids, etc. Many in vitro and in vivo studies demonstrate the neuroprotective effects of the bioactive compounds, however, the clinical trial to examine the neuroprotection of G. lucidum is lacking. The mechanistic studies show that the bioactive compounds can regulate aging-related gene to elongate yeast lifespan, and increase neurotrophin such as Nerve Growth Factor (NGF) and Brainderived neurotrophic factor (BDNF) to protect the neuronal cells death induced by serum deprivation.^12-14

Dictyophora Indusiata

Dictyophora indusiata is an edible as well as medicinal mushroom in Asian countries. This mushroom has the common names as Veiled lady mushrooms or Bamboo mushrooms. Although it has a long history of being consumed in Asian countries, the investigation of the bioactive compounds associated with neurodegenerative diseases is very limited. Until now, dictyophorine A and B have been isolated from the mushroom and can significantly improve the amount of Nerve Growth Factor (NGF) in astroglial cells.15 A more recent study identified dictyoquinazol A, B, and C in D. indusiata, and found that 5 µM dictyoquinazol A, B, and C treatment can reduce excitotoxininduced cortical cell death. The protective effect is in a dose-dependent manner with ~20% for 0.5 µM and >60% for 5 µM.¹⁶

Mycoleptodonoides Aitchisonii

Mycoleptodonoides aitchisonii is an edible mushroom that is called “Bunaharitake” in Japanese. This mushroom is a rare type that has been consumed, which may be the reason that it has not been well investigated for the potential preventive effect against human diseases. Some bioactive compounds have been isolated and identified in this mushroom (Table 1). The treatment of 0.1 µg/ml 3-(hydroxymethyl)-4-methylfuran2(5H)-one and (3R,4S,1’R)-3-(1’-hydroxy-ethyl)-4-methyldihydrofuran-2(3H)-one for 24 hrs significantly (p<0.01) reduced tunimycin-induced Neuro-2a cell death, indicating the protective>< 0.01) reduced tunimycin-induced Neuro-2a cell death, indicating the protective effect against Endoplasmic Reticulum (ER) stress-induced cell death.¹⁷ The treatment of 0.6 µM 5-hydroxy-4-(1-hydroxyethyl)- 3-methylfuran-2(5H)-one and 5-phenylpentane-1,3,4-triol for 24 hrs has the same protective effect to the aforementioned bioactive compounds on ER stressed Neuro-2a cells.¹⁸ The investigation on this mushroom is currently performed only in vitro.

The bioactive small molecules from the aforementioned medicinal mushrooms are summarized in Table 1.

FUTURE RESEARCH

Neurodegenerative disease is difficult to be cured by using the current available therapies. The prevention or delay this disease progress becomes an important therapy. The investigations of isolating and identifying the effective bioactive compounds in medicinal mushrooms that potentially prevent the neurodegenerative disease occurrence provide promising scientific data to demonstrate the potential of medicinal mushrooms as a prevention or treatment to the disease. The studies of the bioactive compounds in these mushrooms are still in early investigation stage. In addition to the aforementioned bioactive compounds in the medicinal mushrooms, various anti-oxidants have been reported in different mushrooms for their potential therapeutic effects on neurodegenerative diseases. For example, mushroom-derived ergothioneine has been confirmed to have anti-oxidative effects in vitro and in vivo. ^19,20 One recent animal study showed oral administration of ergothioneine improved memory and learning abilities of Alzheimer’s disease (AD) model mice.²¹ Until now, most studies have been only performed in cell lines or animal models. Medicinal mushrooms are traditionally consumed in Asian countries. Very limited data come from human studies. Meanwhile, the investigations of certain bioactive compound are not well established. For many potential bioactive compounds, only one or two publications reported the data from very limited experiments.

Table 1: Bioactive compound in medicinal mushrooms that potentially have anti-neurogenerative effects.

It is worth to notice that mushrooms have been traditionally used as medicinal foods in some countries for the therapeutic effects. Meanwhile, the scientific research confirmed multiple potential therapeutic bioactive compounds in mushrooms, which indicates the whole food consumption is an effective approach for the health improvement purpose. However, more investigations on the bioavailability, efficacy, and interactions of bioactive compounds of the whole food are needed to confirm the concept.

It is worth to notice that mushrooms have been traditionally used as medicinal foods in some countries for the therapeutic effects. Meanwhile, the scientific research confirmed multiple potential therapeutic bioactive compounds in mushrooms, which indicates the whole food consumption is an effective approach for the health improvement purpose. However, more investigations on the bioavailability, efficacy, and interactions of bioactive compounds of the whole food are needed to confirm the concept.

Based on the current literature review, both in vitro and in vivo studies are needed for further investigation on the antineurodegenerative effects of the bioactive compounds; further mechanistic studies are needed to provide evidence for these compounds to be potential therapies against neurodegenerative diseases.

CONFLICTS OF INTEREST

The authors whose names are listed immediately below certify that they have NO affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript.

Author Names: Tongtong Xu and Robert B. Beelman

1. Uttara B, Singh AV, Zamboni P, Mahajan RT. Oxidative stress and neurodegenerative diseases: A review of upstream and downstream antioxidant therapeutic options. Current neuropharmacology. 2009; 7: 65. doi: 10.2174/157015909787602823

2. Mattila P, Konko K, Eurola M, et al. Contents of vitamins, mineral elements, and some phenolic compounds in cultivated mushrooms. Journal of Agricultural and Food Chemistry. 2001; 49: 2343-2348. doi: 10.1021/jf001525d

3. Mattila P, Salo-Vaananen P, Konko K, Aro H, Jalava T. Basic composition and amino acid contents of mushrooms cultivated in Finland. Journal of Agricultural and Food Chemistry. 2002;50: 6419-6422. doi: 10.1021/jf020608m

4. Xu T, Beelman B, Lambert D. The cancer preventive effects of edible mushrooms. Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry-Anti-Cancer Agents).2012; 12: 1255-1263. doi: 10.2174/187152012803833017

5. Phan CW, David P, Naidu M, Wong KH, Sabaratnam V. Therapeutic potential of culinary-medicinal mushrooms for the management of neurodegenerative diseases: diversity, metabolite, and mechanism. Critical reviews in biotechnology. 2014; 1-14.
doi: 10.3109/07388551.2014.887649

6. Mori K, Inatomi S, Ouchi K, Azumi Y, Tuchida T. Improving effects of the mushroom Yamabushitake (Hericium erinaceus) on mild cognitive impairment: A double-blind placebo-controlled clinical trial. Phytotherapy Research. 2009; 23: 367-372. doi: 10.1002/ptr.2634

7. Kawagishi H, Zhuang C, Yunoki R. Compounds for dementia from Hericium erinaceum. Drugs of the Future. 2008; 33: 149.
doi: 10.1358/dof.2008.033.02.1173290

8. Nagai K, Chiba A, Nishino T, Kubota T, Kawagishi H. Dilinoleoyl-phosphatidylethanolamine from Hericium erinaceum protects against ER stress-dependent Neuro-2a cell death via protein kinase C pathway. The Journal of nutritional biochemistry. 2006; 17: 525-530.
doi: 10.1016/j.jnutbio.2005.09.007

9. Qi J, Ojika M, Sakagami Y. Termitomycesphins A – D, novel neuritogenic cerebrosides from the edible Chinese mushroom Termitomyces albuminosus. Tetrahedron. 2000; 56: 5835-5841. doi: 10.1016/S0040-4020(00)00548-2

10. Qu Y, Sun K, Gao L, et al. Termitomycesphins G and H, additional cerebrosides from the edible Chinese mushroom Termitomyces albuminosus. Bioscience, biotechnology, and biochemistry. 2012; 76: 791-793. doi: 10.1271/bbb.110918

11. Choi JH, Maeda K, Nagai K, et al. Termitomycamides A to E, fatty acid amides isolated from the mushroom Termitomyces titanicus, suppress endoplasmic reticulum stress. Organic letters. 2010; 12: 5012-5015. doi: 10.1021/ol102186p

12. Weng Y, Lu J, Xiang L, et al. Ganodermasides C and D, two new anti-aging ergosterols from spores of the medicinal mushroom Ganoderma lucidum. Bioscience, biotechnology, and biochemistry. 2011; 75: 800-803. doi: 10.1271/bbb.100918

13. Weng Y, Xiang L, Matsuura A, Zhang Y, Huang Q, Qi J. Ganodermasides A and B, two novel anti-aging ergosterols from spores of a medicinal mushroom Ganoderma lucidum on yeast via UTH1 gene. Bioorganic & medicinal chemistry. 2010; 18:999-1002. doi: 10.1016/j.bmc.2009.12.070

14. Zhang XQ, Ip FC, Zhang DM, et al. Triterpenoids with neurotrophic activity from Ganoderma lucidum. Natural product research. 2011; 25: 1607-1613. doi: 10.1080/14786419.2010.496367

15. Kawagishi H, Ishiyama D, Mori H, et al. Dictyophorines A and B, two stimulators of NGF-synthesis from the mushroom Dictyophora indusiata. Phytochemistry. 1997; 45: 1203-1205. doi: 10.1016/S0031-9422(97)00144-1

16. Lee IK, Yun BS, Han G, Cho DH, Kim YH, Yoo ID. Dictyoquinazols A, B, and C, new neuroprotective compounds from the mushroom Dictyophora indusiata. Journal of natural products.2002; 65: 1769-1772. doi: 10.1021/np020163w

17. Choi JH, Horikawa M, Okumura H, et al. Endoplasmic reticulum (ER) stress protecting compounds from the mushroom Mycoleptodonoides aitchisonii. Tetrahedron. 2009; 65: 221-224. doi: 10.1016/j.tet.2008.10.068

18. Choi JH, Suzuki T, Okumura H, et al. Endoplasmic Reticulum Stress Suppressive Compounds from the Edible Mushroom Mycoleptodonoides aitchisonii. Journal of natural products.2014; 77: 1729-1733. doi: 10.1021/np500075m

19. Dubost NJ, Ou B, Beelman RB. Quantification of polyphenols and ergothioneine in cultivated mushrooms and correlation to total antioxidant capacity. Food Chem. 2007; 105: 727-735. doi: 10.1016/j.foodchem.2007.01.030

20. Weigand-Heller AJ, Kris-Etherton PM, Beelman RB. The bioavailability of ergothioneine from mushrooms (Agaricus bisporus) and the acute effects on antioxidant capacity and biomarkers of inflammation. Preventive medicine. 2012; 54: S75-S78.  doi: 10.1016/j.ypmed.2011.12.028

21. Yang NC, Lin HC, Wu JH, et al. Ergothioneine protects against neuronal injury induced by β-amyloid in mice. Food and Chemical Toxicology. 2012; 50: 3902-3911. doi: 10.1016/j.fct.2012.08.021