Drugs of the Future 2008, 33(2): 149-155 © 2008 Prous Science, S.A.U. or its licensors. All rights reserved. CCC: 0377-8282/2008 DOI: 10.1358/dof.2008.033.02.1173290 Review Article Compounds for dementia from Hericium erinaceum Hirokazu Kawagishi1,2,*, Cun Zhuang3 1Graduate School of Science and Technology, Shizuoka University, Shizuoka 422-8529, Japan; 2Department of Applied Biological Chemistry, Faculty of Agriculture, Shizuoka University, Shizuoka 422-8529, Japan; 3Bio Research Institute, New Jersey, USA. *Correspondence: [email protected] CONTENTS protection against neuronal cell death caused by oxida- tive or endoplasmic reticulum (ER) stress (8-10); 3) anti- Abstract . tumor activity (11); 4) anti-HIV activity (12); 5) immune Introduction . enhancement (13-15); 6) hemagglutinating activity (16, NGF and AD . 17); 7) cytotoxicity against cancer cells (18-20); 8) antimi- Hericenones . crobial activity (21-23); 9) hypoglycemic effects (24); and Erinacines . Bioactivities of hericenones and erinacines . 10) hypolipidemic effects (25). Aβ and AD . Alzheimer’s disease (AD) is the most common form of DLPE . dementia, causing memory loss, language deterioration, Bioactivities of DLPE . impaired ability to manipulate visual information mentally, Preliminary clinical trials . poor judgement, confusion, restlessness and mood Conclusions . swings due to progressive neurodegeneration. It eventu- References . ally leads to the loss of cognition, personality and func- tion. It has been reported that the susceptibility to AD is closely related to a number of factors, including age, Abstract genes, lack of NGF and excessive accumulation of Aβ. Conventional treatments for AD only address the symp- Our group has been conducting a search for com- toms, but there is presently no cure. For this reason, heri- pounds for dementia derived from medicinal mush- cenones, erinacines and dilinoleoyl-phosphatidylethanol- rooms since 1991. A series of benzyl alcohol deriva- amine (DLPE), isolated from H. erinaceum and showing tives (named hericenones C to H), as well as a series significant activities in inducing the synthesis of NGF or of diterpenoid derivatives (named erinacines A to I) were isolated from the mushroom Hericium erinaceum. protecting against neuronal cell death caused by Aβ, ER These compounds significantly induced the synthesis stress or oxidative stress, are attracting great attention of nerve growth factor (NGF) in vitro and in vivo. In a and may be developed into medicinal products or dietary recent study, dilinoleoyl-phosphatidylethanolamine supplements used for preventing and improving dementia (DLPE) was isolated from the mushroom and was in general and AD in particular. In this review, we discuss found to protect against neuronal cell death caused by the isolation and bioactivities of these compounds, and β-amyloid peptide (Aβ) toxicity, endoplasmic reticulum the possible clinical application of the fungus. (ER) stress and oxidative stress. Furthermore, the results of preliminary clinical trials showed that the NGF and AD mushroom was effective in patients with dementia in improving the Functional Independence Measure (FIM) NGF, one of a family of neurotrophins that induce the score or retarding disease progression. survival and proliferation of neurons, plays an important role in the repair, regeneration and protection of neurons. It has been suggested that NGF may be used to treat AD (26). One report described how a woman with AD experi- Introduction enced improvement in symptoms (including impaired Hericium erinaceum is an edible and medicinal mush- mental ability) after the administration of NGF directly to room, known in Japan as ‘Yamabushitake’, in China as the brain using a catheter (27). However, since NGF is a ‘Hou Tou Gu’ and in Europe and the United States as protein that cannot pass through the blood-brain barrier ‘Lion’s Mane’. It has been demonstrated that H. eri- (BBB) and needs to be injected directly into the brain to naceum exerts important bioactivities, including: 1) the be effective, it is a high-risk treatment. A safer therapy for induction of nerve growth factor (NGF) synthesis (1-7); 2) this disease would be a compound that could be admin- inhibition of the cytotoxicity of β-amyloid peptide (Aβ) and istered orally, pass through the BBB and so induce NGF 2 Compounds for dementia from Hericium erinaceum synthesis inside the brain. Even if this compound could Hericenones not pass through the BBB, it might still be beneficial for disorders of the peripheral nervous system, since NGF The fruiting bodies of H. erinaceum were extracted has a similar effect on neurons in that system. with acetone at room temperature. The acetone extract Based on this concept, a search for natural inducers was concentrated under reduced pressure, and then frac- of NGF synthesis has been conducted worldwide, and tionated by solvent partition between chloroform and several compounds with a lower molecular weight were water. The chloroform-soluble layer was further fraction- found to have such bioactivity. Among those bioactive ated and purified by various chromatographies, and six compounds, hericenones and erinacines from H. eri- compounds, named hericenones C to H, were obtained naceum were the first natural compounds and were found (1, 2). As shown in Figure 1, hericenones C to H (1-6) are to possess remarkable activities. benzyl alcohol derivatives having simple fatty acids. OH O H H O O CH O 3 CH3 O OH R OH R O CH3 H C O O 3 OH CH3 CH3 H O CH3 O CH3 O CH CH 3 3 O H C CH Hericenone C (1) R = palmitoyl Hericenone F (4) R = palmitoyl 3 3 Hericenone D (2) R = stearoyl Hericenone G (5) R = stearoyl Erinacine A (7) Hericenone E (3) R = linoleoyl Hericenone H (6) R = linoleoyl OH O O OH O OH O OH O O CH3 CH3 CH3 H C OH OH 3 OH H3C H3C O O H H OH H H H O O O H3C CH3 H3C CH3 H3C CH3 CH3 Erinacine B (8) Erinacine C (9) Erinacine D (10) H O O CH O O CH O 3 CH O 3 CH 3 OH H3C 3 H3C OH OH H3C OH H H H H H H3C H H H OH OH O O H OH OH OH OH H3C CH3 H3C CH3 Erinacine E (11) Erinacine F (12) Erinacine G (13) OH OH O O OH CH3 O OH H C CH O OH 3 H C 3 CH3 3 OH H3C OH O O CH3 H + H O Na H O O H3C CH3 O CH3 O H3C CH3 H3C CH3 O Erinacine H (14) Erinacine I (15) Erinacine P (16) Fig. 1. Hericenones and erinacines, inducers of NGF synthesis isolated from Hericium erinaceum. Drugs Fut 2008, 33(2) 3 Among these compounds, hericenones F to H (4-6) are Bioactivities of hericenones and erinacines probably formed by cyclization between the phenolic hydroxyl and the side-chain of hericenones C to E (1-3), Within the brain, the neuron and astroglia are respon- and exist in racemic forms. sible for NGF production. It has been reported that the neuron controls NGF synthesis in order to maintain func- tion in the mature brain, while the astroglia play the same Erinacines role when the brain is growing or damaged. Therefore, The mycelia of H. erinaceum were cultivated in a tank primary astroglia derived from rat cerebral cortex were for 4 weeks, and the mycelia and the culture media were used in screening for bioactive compounds that induce separated by centrifugation. The mycelia obtained were the synthesis of NGF. The above compounds were extracted with 85% ethanol at room temperature. The added to these cells, maintained in a 96-well microplate, ethanol extract was concentrated under reduced pres- at various concentrations for 24 h, after which NGF sure, and then fractionated by solvent partition between secreted into the culture media was measured by an ethyl acetate and water. The ethyl acetate-soluble layer enzyme immunoassay (29-32). Hericenones C to E (1-3) was further fractionated and purified with various chro- induced the synthesis of NGF in vitro. In the presence of matographies, and nine compounds, named erinacines A 33 µg/ml of hericenones D (2), E (3) and C (1), the to I (7-15), were obtained (Fig. 1) (3-6). Erinacines A to I mouse astroglial cells secreted 23.5 ± 1.0, 13.9 ± 2.1 are diterpenoid derivatives with different chemical struc- and 10.8 ± 0.8 pg/ml of NGF, respectively. Hericenone D tures from those of the hericenones. In addition, it has was as effective as epinephrine (a potent inducer used been reported that another compound, named erinacine P as a positive control) (1). It is interesting to note that the (16), was isolated from the mycelia of H. erinaceum (28). difference in activity among these compounds was Erinacine P is considered to be a precursor of erinacines dependent on the chain length and the double bond of A (7) and B (8), and can be successfully converted to the fatty acid part. As shown in Figure 3, erinacines A to these compounds by a biomimetic reaction (Fig. 2). G (7-13) were more potent inducers of NGF synthesis OH OH O O O OH O OH CH CH H C 3 H C 3 3 OH ii 3 OH erinacines E-G H [1,5]-H shift H H O O H C CH 3 3 H3C CH3 7 Path B Path A Path C elimination of the nucleophile elimination dienolization of the acetate elimination of 2'-O- OH OH O O OH O O OH O O OH CH3 CH CH H C 3 H C 3 3 OH H3C OH 3 OH i or ii O (ii) O O 1,4-addition of 2'-OH 1,4-addition of [Nu] H - H H elimination of AcO H elimination of 2'-O - H H O CH O Nu+ H C CH 3 H C CH 3 3 H3C CH3 3 3 O 16 8 Fig.