Neurological Activity of Lion’s Mane (Hericium erinaceus) Kevin Spelman, PhD, MCPPa ©2017, Kevin Spelman, PhD, MCPP Elizabeth Sutherland, NDb Journal Compilation ©2017, AARM DOI 10.14200/jrm.2017.6.0108 Aravind Bagade, MDc ABSTRACT Hericium erinaceus, most commonly known as lion’s mane, is an edible fungus, with a long history of use in Traditional Chinese Medicine. The mushroom is abundant in bioactive compounds including β-glucan polysaccharides; hericenones and erinacine terpenoids; isoindolinones; sterols; and myconutrients, which potentially have neuroprotective and neuroregenerative properties. Because of its anti-inflammatory properties and promotion of nerve growth factor gene expression and neurite (axon or dendrite) outgrowth, H. erinaceus mycelium shows great promise for the treatment of Alzheimer’s and Parkinson’s diseases. The fungus was well tolerated in two clinical studies, with few adverse events reported. Keywords: Lion’s mane; Neuroregeneration; Neurodegeneration; Neuroprotection; Neurotropins; Neurotrophic; Alzheimer’s disease; Parkinson’s disease; Multiple Sclerosis; Nerve growth factor aCorresponding author: Health, Education & Research, POB 599, Ashland, OR 97520, USA, Tel.: +1-541-708-3002; E-mail: [email protected] bAdjunct faculty National University of Natural Medicine, Portland, OR, USA cExecutive Secretary and Researcher, Ayurveda Interdisciplinary Research Minds Association, Mysore, India Journal of Restorative Medicine 2017; 6: page 19 Lion’s Mane Neurological Activity INTRODUCTION Ancient, traditional, and modern cultures around is called hóu tóu gū (“monkey head mushroom”) the world have known about the nutritive and in Chinese8 and yamabushitake (“mountain monk medicinal properties of mushrooms for centu- mushroom”) in Japanese. In Chinese and Japanese ries. As early as 450 BCE, the Greek physician medical systems, it has traditionally been used to Hippocrates identified mushrooms as potent fortify the spleen, nourish the gut, and also as an anti-inflammatory agents, useful for cauterizing anticancer drug.9 Lion’s mane is said to be nutri- wounds. In the East, reverence for fungi is evident tive to the five internal organs (liver, lung, spleen, in the Chinese description of ling zhi (Ganoderma heart, and kidney), and promotes good digestion, lucidum), as the “spirit plant,” believed to provide general vigor, and strength. It is also recommended longevity and spiritual potency. for gastric and duodenal ulcers, as well as chronic gastritis (in prepared tablet form).10 The mushroom Modern medicine has been slower to catch on to is also known for its effects on the central nervous the immense potential of fungi. Despite Fleming’s system, and is used for insomnia, vacuity (weak- 1929 discovery of penicillin,1 and the subsequent ness), and hypodynamia, which are characteristic implementation of the fungi-chemical as a block- symptoms of Qi deficiency in Traditional Chinese buster pharmaceutical in the 1940s,2 it is only medicine (TCM). in the last few decades that medical science has looked beyond the antimicrobial and cholesterol- lowering properties of fungi for other potential CHEMISTRY applications. Clinicians now have greater access to myce- The bioactive metabolites of H. erinaceus can be lium extracts, which are used clinically for their classified into high molecular weight compounds, cytotoxic, antineoplastic, cardiovascular, anti- such as polysaccharides, and low molecular 3–5 inflammatory, and immune-modulating activities. weight compounds, such as polyketides and Functional studies and chemical assays also support terpenoids.10,11 their potential to act as analgesic, antibacterial, antioxidant, and neuroprotective agents. A number of mushrooms, including Sarcodon scabrosus, POLYSACCHARIDES Ganoderma lucidum, Grifola frondosa, and Fungal polysaccharides are found mainly in cell Hericium erinaceus are reported to have activi- walls, and are present in large quantities in both 6 ties related to nerve and brain health. Hericium fruiting bodies and cultured mycelium. Hericium erinaceus, a member of the Herinaceae family, is a erinaceus fruiting bodies (HEFB) contain immu- culinary and medicinal mushroom. Both the myce- noactive β-glucan polysaccharides, as well as lium and fruiting bodies of H. erinaceus have been α-glucans and glucan-protein complexes.12 A total shown to have therapeutic potential for brain and of more than 35 H. erinaceus polysaccharides 7 nerve health. The unique neurological activities of (HEP) have been extracted to date from cultured, this fungus are the subject of this review. wild-growing, or fermentative mycelia and fresh/ dried fruiting bodies. Of these β-glucans represent the main polysaccharides. HEP are composed of TRADITIONAL USE OF LION’S xylose (7.8%), ribose (2.7%), glucose (68.4%), arabinose (11.3%), galactose (2.5%), and mannose MANE (H. ERINACEUS) (5.2%).4 Four different polysaccharides isolated from the H. erinaceus sporocarp show antitumor Hericium erinaceus (lion’s mane, yamabushi- activity: xylans, glucoxylans, heteroxyloglucans, take, or bearded tooth carpophore) grows on old and galactoxyloglucans.5 Chemical analysis shows or dead broadleaf trees, and is used as both food that the total content of HEP found in fruiting bod- and medicine in parts of Asia. The fruiting body ies is higher than that in mycelium. Table 1 lists the Journal of Restorative Medicine 2017; 6: page 20 Lion’s Mane Neurological Activity Table 1: Polysaccharides: source and composition. Polysaccharides No. Isolated from Composition (FI0-a, FI0-a-α, FI0-a-β, FI0-b, 6 Fresh fruiting bodies of H. Xylans, glucoxylans, FII-1, FIII-2b) erinaceus heteroxyloglucans, and galactoxyloglucans AF2S-2, BF2S-2 2 Fresh fruiting bodies Backbone of β-(l→6)-linked D-glucopyranosyl residues, and had β-(1→3) and β-(l→6) glucosidic linkages Heteropolysaccharides (HEPA1, 3 Mycelium Glucose HEPA4, HEPB2) Water extractable polysaccharides 2 Aqueous extract Glucose and galactose (HPA and HPB) Water soluble polysaccharide 1 H. caput-medusae Glucose and galactose (HPI) Neutral heteropolysaccharides 2 Fruiting bodies Glucose (HEP-1 and HEP-4) Glucans HEP-3 (β-glucan) and 2 Fruiting bodies Glucose HEP-5 (α glucan) Acidic polysaccharide (HEP-2) 1 Fruiting bodies Uronic acid Heteropolysaccharide (HPB-3) 1 The maturating-stage IV, I-fucose, d-galactose and V, and VI fruiting body d-glucose Homopolysaccharides, a neutral 1 Fermentative mycelia Glucose glucan (HPP) polysaccharides along with their source and chemi- oxygen containing group. Terpenoids make up over cal composition. 60% of products in the natural world.15,16 Studies of the polysaccharides found in A variety of diterpenes and sesterpenes are found H. erinaceus reveal a number of activities. For in the fruiting body and fermenting mycelium of example, extracellular and intracellular polysac- H. erinaceus.17 Of particular pharmacological inter- charides showed a protective effect on oxidative est are two classes of terpenoid compounds thus far hepatotoxicity in mice.11 Neuroprotective effects of known to occur only in Hericium spp.: hericenones HEPs were observed in an in vitro model of cells (C–H), a group of aromatic compounds isolated that were toxic from amyloid β plaque formation. from the fruiting body; and erinacines (A–I), a In this model, HEPs decreased the production of group of cyathane-type diterpenoids found in the reactive oxygen species from 80% to 58% in a dose- mycelium.18 Both groups of substances easily cross dependent manner, and increased the efficacy of free the blood-brain barrier, and have been found to have radical scavenging. HEPs also promoted cell viabil- neurotrophic and in some cases neuroprotective ity and protected cells against apoptosis induced effects.19 Erinacines (A–I) have demonstrated induc- by amyloid β plaque formation.13 HEPs decreased tion of nerve growth factor (NGF) synthesis.20 Table blood lactic acid, serum urea nitrogen, tissue glyco- 2 lists the terpenoids, sesterpenes, and diterpenoids gen, and malondialdehyde, further supporting the along with their source and chemical composition. beneficial role of HEPs on oxidative stress.14 STEROLS TERPENOIDS: SESTERPENES, AND Ten erinarols, described as erinarol A–J, five DITERPENOIDS ergostane-type sterol fatty acid esters, and ten Terpenoids are a class of naturally occurring ergostane-type sterols have been identified in the hydrocarbons that consist of terpenes attached to an fruiting body of H. erinaceus.21 Sterols, such as Journal of Restorative Medicine 2017; 6: page 21 Lion’s Mane Neurological Activity Table 2: Sesterpenes and diterpenoids: source and composition. Terpenoids Isolated from Composition Hericenones Fresh fruiting bodies of H. erinaceus Erinacerins C–L together with Erinacines Mycelia (E)-5- (3,7- methylocta-2,6-dien- 1-yl)-4-hydroxy-6-methoxy-2- phenethylisoindolin-1-one Diterpenoids Fresh fruiting bodies of H. erinaceus Erinacines A–I Isoindolinones Fresh fruiting bodies of H. erinaceus Erinaceolactams A–E, hericenone A, hericenone J, N-De phenylethylisohericerin, erinacerin A, and hericerin ergosterol confer antioxidative properties.21,22 polysaccharide), failed to show a protective effect.27 Hericium erinaceus has been found to be the most Although it is challenging to draw clinically rele- potent in vitro inhibitor of both low-density lipo- vant conclusions from in vitro studies, this suggests protein (LDL) oxidation and HMG Co-A reductase that water extracts would not have a neuroprotec- activity, suggesting therapeutic potential