Human neurodegenerative diseases, such as Alzheimer’s, Huntington’s, and Parkinson’s disease, are disrupting neuronal populations in adults worldwide. The discovery and development of neuroactive compounds from medicinal mushrooms with the potential to improve nerve functioning has been extensively studied. Mushrooms, such as Antrodia camphorata, Ganoderma spp., Hericium erinaceus, Lignosus rhinocerotis and Pleurotus giganteus, have a long history of use in enhancing the peripheral nervous system. Nerve growth factors are important for the survival, maintenance, and regeneration of specific neuronal populations in the adult brain. It has been demonstrated that neurodegenerative diseases mostly occur because of the disappearance of nerve growth factors. Therefore, scientists have been attempting for over 20 years to discover fungi-derived neuroactive components which are able to cross the blood–brain barrier and induce the production of nerve growth factors.
Most of the potential neuroactive compounds, which may aid in the prevention or therapy of neurodegenerative diseases, have been discovered in Hericium erinaceus. This medical mushroom is known to produce two unique terpenoid classes, namely hericenones and erinacines, from its fruiting body and mycelia, which can stimulate synthesis of the nerve growth factor via the TrkA/Erk1/2 pathway. Not only does H. erinaceus induce nerve growth factors or nerve regeneration, but it has also been shown to improve digestive functioning and effect relief from gastritis while providing immune-support, such as anti-inflammatory and anti-oxidant activities. Several studies have demonstrated that hericenones such as hericenone A (19) and erinacines (erinacine C (20) induce the synthesis of nerve growth factors in vivo and in vitro (Thongbai et al. 2015). Wittstein et al. (2016) discovered corallocins A–C, a nerve growth and brain-derived neurotrophic factor inducing metabolites, from the related Hericium coralloides in cell based bioassays, while Rupcic et al. (2018) discovered two new erinacine derivatives from mycelial cultures of H. erinaceus and H. flagellum. Additional studies have revealed neuroactive activities in extracts from medicinal mushrooms that induce nerve growth factors, but the active principles remain to be identified. For instance, the aqueous sclerotium extract from the Malaysian medicinal mushroom, Lignosus rhinocerotis, contained neuroactive compounds that have been demonstrated to stimulate neurite outgrowth in vitro (Eik et al. 2012). Similarly, aqueous extracts of fruiting bodies of species referred to as “Ganoderma lucidum” (questionable identification because the report was from Asia where this species does not actually occur) and G. neo–japonicum were also effective at stimulating neurite outgrowth (Seow et al. 2013). Pleurotus giganteus was found to contain a high concentration of uridine, which has also shown nutritional outgrowth stimulatory effects (Phan et al. 2012). These results may give rise to a more systematic study of the phenomenon in the future.
The family Hericicaceae comprises other genera and species, such as Laxitextum incrustatum Mudalungu et al. (2016) and Dentipellis fragilis (Mitschke 2017), which were proven to contain compounds of the erinacine type; these cyathane terpenoids may constitute family-specific markers. On the other hand, Bai et al. (2015) have reported cyathane diterpenoids as nerve growth factor enhancers from cultures of a Cyathus species, and even the cyathanes from the fruit bodies of the mycorrhizal basidiomycetes of the genus Sarcodon seem to have similar effects (Cao et al. 2018). It should therefore be worthwhile to study genera that are known to produce cyathanes, as well as representatives of other mushroom genera related to Hericium, including Amylosporus and Wrightoporia, for such phenomena. This examination may lead to the discovery of additional novel neurotropic compounds. Reliable screening systems, as well as genetic models of human neurodegenerative diseases, are now available for in vivo cell biological analysis of disease progression and intervention.
While the mode of action of the hericenones, corallocins and erinacines remains to be clarified, a very important drug that constitutes a mimetic of a fungal metabolite should be mentioned in this context. Fingolimod (21) is a product of total synthesis that has been discovered during the course of a mimetic synthesis program that used as template myriocin (22), a compound produced by the insect associated ascomycete Isaria sinclairii (Strader et al. 2011). Fingolimod (sold under the brand Gilenya), is a potent immunosuppressant that was approved in 2010 by the U.S. Federal Drug Association as a new treatment for multiple sclerosis. Fingolimod is phosphorylated in vivo by sphingosine kinase 2, and the resulting metabolite binds to the extracellular G protein-coupled receptors, sphingosine 1-phosphates. This prevents the release of lymphocytes from lymphoid tissue and therefore can suppress the immune system. Aside from its proven effects against the symptoms of multiple sclerosis, the compound can also potentially be used in the therapy of cancer and during organ transplants. Likewise, additional potential usages for the erinacines and hericenones may become conceivable once the biochemical and molecular mechanisms by which they exert their activities in biological systems have been elucidated.