Written by Renata Filiaci, MS Health and Wellness

Introduction

The lion’s mane mushroom, Hericium erinaceus, is a culinary mushroom traditionally used in Eastern Asian medicine and cuisine. It is a eukaryotic spine fungus that grows on the trunks, branches, and stumps of trees; the fruiting body is typically used, although studies have been finding benefits from using the beds of the mushroom, which are usually thrown out (Raman, Lakshmanan, John, Zhijian, Periasamy, David, Naidu, & Sabaratnam, 2015). The lion’s mane mushroom is known for its pharmacological activity as it has been used as an antitumor and immunomodulation, anti-gastric ulcer, anti-oxidation, hepatoprotection, anti-hyperlipidemia, anti-hyperglycemic, anti-fatigue and anti-aging due to its bioactive constituents, β-glucan polysaccharides, monosaccharides, hericenones, and erinacine terpenoids, and myconutrients (Spelman, Sutherland, & Bagade, 2017).

Currently, the lion’s mane mushroom has been examined for its highly efficient neuroprotection and neuro-regeneration activity related to the central and peripheral nervous system. There is growing evidence that the decline and deprivation of neurotrophins (nerve growth factor) is an essential factor in the pathogenesis of neurodegenerative diseases (Zhang, Cao, Kubo, Harada, Yan, Fukuyama, & Gao, 2017). To endure optimal neuronal health, it is ideal to have proper endoplasmic reticulum function, reduce oxidative and mental stress, protect neurotrophins (nerve growth factor), and prevent amyloid B(25-35) buildup on the hippocampus. Consuming mushroom extracts, herbal supplements, or powder, it is presented as safe; however, with little evidence, it is best to use precaution when pregnant or breastfeeding (Sabaratnam, Wong, Naidu, & David, 2013). The purpose of this research is to assess whether the use of lion’s mane mushroom for neurological health was beneficial.

Results

In a study by Ueda, Kodani, Kubo, Masuno, Sekiya, Nagai, and Kawagishi (2009), the authors researched and assessed compounds from lion’s mane mushroom beds and its suppressive effects on endoplasmic reticulum stress. The endoplasmic reticulum (ER) is a membrane which synthesizes proteins and lipids as well as metabolizes fats (Banasik & Copstead, 2019). ER stress can be caused by a number of disturbances, such as physiological and pathological stressors increasing secretory load and presenting mutated proteins that can’t correctly fold; this action induces excessive apoptosis in neural cells, which leads to neurodegenerative disorders (Lin, Walter, & Yen, 2008; Xu, Bailly-Maitre, & Reed, 2005). The beds of the mushrooms are usually discarded after harvesting of the fruiting bodies has taken place. The compounds examined from the lion’s mane mushroom beds were methyl 4-hydroxy-3-(3-methyl butanol) benzoate, 2-chloro-1,3-dimethoxy-5-methylbenzene, methyl 4-chloro-3,5-dimethoxybenzaldehyde, and 4-chloro-3,5-dimethoxybenzaldehyde (compounds 1-4). After inhibiting proper ER function and inducing ER stress by adding tunicamycin or thapsigargin to Neuro2a cells, which are mouse neuroblastoma cells, the researchers combined the isolated compounds 1-4 and evaluated its neuroprotective activity (Ueda, Kodani, Kubo, Masuno, Sekiya, Nagai, & Kawagishi, 2009; ATCC, 2018). Compounds 1, 2, and 4 showed favorable results against ER stress induced by both tunicamycin or thapsigargin and compound 3 showed useful effects against ER stress induced by thapsigargin. Although compound 3 wasn’t protective against both triggers, all compounds presented defense mechanisms against ER stress (Ueda, Kodani, Kubo, Masuno, Sekiya, Nagai, & Kawagishi, 2009).

The authors, Nagano, Shimizu, Kondo, Hayashi, Sato, Kitagawa, & Ohnuki (2010), evaluated the bioactive compounds of lion’s mane mushroom and their effects after given to thirty women with indefinite complaints, poor sleep quality, menopause, and depression. Based on a study performed by Nevell, Zhang, Aiello, Koenen, Galea, Soliven, Zhang, Wildman, and Uddin (2014), after analyzing 86 participants with the major depressive disorder, the researchers saw the persistent activation of the endoplasmic reticulum stress response pathway. The researchers believe that the isolated bioactive compounds of the lion’s mane mushroom, diterpenoids, stimulate and enhance neurotrophins (nerve growth factor) which affects the viability of cholinergic neurons; if cholinergic neurons are operating successfully, improved cognitive impairment, antidepressant, and antianxiety activity have been observed (Nagano, Shimizu, Kondo, Hayashi, Sato, Kitagawa, & Ohnuki, 2010).  The thirty women were randomly assigned to a group that received lion’s mane mushroom cookies or a placebo group and evaluated for four weeks. After the four week trial, the women were given questionnaires: the Kupperman Menopausal Index, the Center for Epidemiologic Studies Depression Scale, the Pittsburgh Sleep Quality Index, and the Indefinite Complaints Index. The Kupperman Menopausal Index, the Center for Epidemiologic Studies Depression Scale, and the Indefinite Complaints Index scores were significantly improved in the lion’s mane mushroom group compared to the placebo group, which provides the possibility that lion’s mane reduces menopausal symptoms, depression, anxiety, and indefinite complaints (Nagano, Shimizu, Kondo, Hayashi, Sato, Kitagawa, & Ohnuki, 2010).

The researchers Brandalise, Cesaroni, Gregori, Repetti, Romano, Orrù, Botta, Girometta, Guglielminetti, Savino, and Rossi (2017) analyzed the use of lion’s mane mushroom dietary supplementation and hippocampal neurotransmission in vivo wild-type male mice with Alzheimer’s disease. The hippocampus is a part of the limbic system and is associated with learning, memories, and emotions; altered neurogenesis in the hippocampus has been linked to the onset of Alzheimer’s disease (Mu & Gage, 2011). The mice were split into two groups and evaluated for two months; the control mice received 5% dextrin dietary supplementation (dx mice), and the Hericium erinaceus treated mice (Hr mice) received 5% “Micotherapy Hericium” supplement. The supplement “Micotherapy Hericium” consisted of Hericium erinaceus mycelium and fruiting body extract with a high polysaccharide content.  Brennan (2016) associates mushroom polysaccharide content with health-promoting properties, such as anti-obesity, antidiabetic, anti-carcinogenic, antimicrobial, and antiviral effects. The researchers performed behavioral tests on the mice, which entailed an emergence test and novel object recognition test. Each test presented positive results from the Hr mice group; the Hr mice obtained an increase in novelty-seeking behavior and recognition memory. The H. erinaceus supplement increased frequency, amplitude, and neurotransmitter release of the hippocampal CA3 pyramidal neurons, which decreased the failure rate in mice (Brandalise, Cesaroni, Gregori, Repetti, Romano, Orrù, Botta, Girometta, Guglielminetti, Savino, & Rossi, 2017).

Mori, Obara, Moriya, Inatomi, and Nakahata (2011) assessed the use of the lion’s mane mushroom on amyloid B(25-35) peptide in mice. Amyloid proteins accumulate in the liver, spleen, kidneys, and other tissues as a result of certain diseases as well as are found in patients with Alzheimer’s disease and dementia (Millucci, Ghezzi, Bernardini, & Santucci, 2010). The continuous aggravation of the nerve growth factor promotes the loss of cholinergic neurons influencing the development of senile plaques and neurofibrillary tangles, in which amyloid B(25-35) peptide is present. The authors split mice into four groups, two groups were treated with amyloid B(25-35) peptide and fed a control diet, and two groups were treated with amyloid B(25-35) peptide and fed a diet with lion’s mane mushroom powder. Similarly to the study performed by Brandalise et al. (2017), on day 21, the mice performed two tests: the Y-maze spatial short-term memory test and the novel object recognition visual memory test. The mice that were fed a control diet resulted in a significant decrease in alternation behavior spent more time exploring the novel object and were impaired in visual recognition memory. The mice fed a diet with lion’s mane mushroom prevented cognitive deficits and amyloid B(25-35) impairment due to the active isolated constituent, hericenones, inducing nerve growth factor mRNA in the mouse hippocampus (Mori, Obara, Moriya, Inatomi, & Nakahata, 2011).

Zhang, An, Hu, Teng, Wang, Qu, Liu, Yuan, and Wang (2016) designed a research study that explored the effects of H. erinaceus (HE) mycelium polysaccharide-enriched extract. The researchers evaluated the extract used on glutamate-damaged rat pheochromocytoma (PC12) apoptosis models and Alzheimer’s disease mouse models. Rat PC12 cells are derived from a tumor in the adrenal medulla and used because of their neuronal mechanisms, such as the ability to produce neurons and display synapse formation (Westerink & Ewing, 2007).  Glutamate is derived from dietary sources; an excessive amount can cause calcium overload, unnecessary apoptosis, oxidative stress, and excitatory neurotoxicity via the mitochondrial pathway. Proper mitochondria function in neurons is necessary for membrane excitability and intricate neurotransmission (Kann & Kovacs, 2007). After evaluation, the researchers calculated positive results. PC12 cells induced with HE extract had enhanced differentiation in the neurons, improved cell viability, presented beneficial mitochondrial activity, as well as reduced calcium overload caused by glutamate. HE extract used on Alzheimer’s mouse models had increased horizontal and vertical movements pertaining to behaviors, had a significantly less escape time in the maze test than the mice with Alzheimer’s disease, and improved central cholinergic system function (Zhang, An, Hu, Teng, Wang, Qu, Liu, Yuan, & Wang, 2016).

The researchers Zhang, Cao, Kubo, Harada, Yan, Fukuyama, and Gao (2017) assessed two isolated compounds and their neuroprotective and neural stimulatory effects on PC12 cells and TrkA/Erk1/2 Pathway. Erk1/2 is a group of a protein kinase that mediates proper apoptosis and cell proliferation (Mebratu & Tesfaigzi, 2009). TrkA is a receptor activated by Erk1/2 which regulates neuronal survival in the nervous system, like nerve growth factor (Uren & Turnley, 2014). Current conventional medicine used to induce nerve growth factor doesn’t cross the blood-brain barrier which makes it harder to treat neurodegenerative disease. The constituents, hericenones, and erinacine, are determined to be eligible to cross the blood-brain barrier. The researchers isolated specific compounds from the lion’s mane mushroom, 4-chloro-3,5-dimethoxybenzoic methyl ester and erinacine A. After examination, the results revealed that the bioactive compounds protected deprivation of nerve growth factor and promoted neurite outgrowth in PC 12 cells as well as induced neuritogenesis in rat cortex neurons (Zhang, Cao, Kubo, Harada, Yan, Fukuyama, & Gao, 2017).

Correspondingly to the study performed by Zhang et al. (2017), Raman, Lakshmanan, John, Zhijian, Periasamy, David, Naidu, and Sabaratnam (2015) reported using biosynthesized gold nanoparticles (AuNP) from Hericium erinaceus (HE) extract on neurite outgrowth of rat PC12 cells. Biosynthesized AuNP is a small in size, environmentally friendly, biological method used in different chemical environments, such as cell cultures or the human bloodstream, to understand drug delivery and material synthesis because of their ability to cross the blood-brain barrier. Degeneration in the central and peripheral nervous system has been linked to neurodegenerative diseases like Alzheimer’s, Parkinson’s, and dementia, in which researchers have confirmed neurotrophic activity in HE. Researchers are also determining that the bioactive constituents, polysaccharides, monosaccharides, and soluble protein, of HE, can protect the nervous system in rats. In this study, rat PC12 cells were incubated with 200, 400, or 600 ng/ml of HE extract AuNP for 72 hours. Neurite outgrowth and neural stimulation in PC12 cells were best achieved with 600 ng/ml of HE extract AuNP because of response to the interaction between nerve growth factor and HE. However, neurite-bearing cells reacted better to 400 ng/ml of HE extract AuNP. These achievements result in neuroprotective and neuro-regenerative effects in both the central and peripheral nervous system through activation of TrkA/Erk1/2 with a small sized substance that crosses the blood-brain barrier mimicking nerve growth factor (Raman, Lakshmanan, John, Zhijian, Periasamy, David, Naidu, & Sabaratnam, 2015).

The authors, Wong, Naidu, David, Abdulla, Abdullah, Kuppusamy, and Sabaratnam (2011), assessed the use of lion’s mane mushroom on axonotmesis rat models from crush injury. Axonotmesis, caused by a crush injury, is initiated by the physical crushing of Schwann cells and axons of the peripheral nervous system resulting in sensory, motor, and autonomic paralysis (Nerve Injury Team, 2018; Rajagopalan, 2011). By using female Sprague-Dawley rat models, the researchers gave the rat’s oral administration of lion’s mane mushroom extract to promote functional recovery of axonotmetic peroneal nerve. To determine whether the extract achieved accurate results, peroneal functional index examinations were performed before and after surgery on the control rats and extract rats. The group of rats that received mushroom extract had a quicker onset of hind limb function and regeneration of axons as well as reinnervation of motor endplates in extensor digitorum longus muscle (Wong, Naidu, David, Abdulla, Abdullah, Kuppusamy, & Sabaratnam, 2011).

Discussion

The evidence determined through the access of studies about the benefits of the lion’s mane mushroom supports the notion that lion’s mane mushroom is essential in aiding in neurological health. The lion’s mane helps reduce endoplasmic reticulum stress, which is beneficial in reducing degradation of neuronal function and neurodegenerative disorders.

Also, the lion’s mane mushroom can be used to decrease menopausal symptoms, depression, and anxiety, limiting endoplasmic reticulum stress as well as the use of prescription drugs like antidepressants; taking mushroom extract or supplements could benefit mental health patients.

Mice that were fed “Micotherapy Hericium” showed positive results in hippocampal function, which pertains to memory and emotions, something significantly lost in Alzheimer’s and dementia patients as well as decreases chance of failure, which could indicate a better quality of life in patients with neurodegenerative diseases. Constituents, such as hericenones and erinecine, ameliorate pathologies as well as protect, maintain, and enhance survival of neurotrophins (NGF), which fight against the onset of neurodegenerative diseases such as Parkinson’s, Alzheimer’s, and Huntington’s. Lion’s mane mushroom maintains and stimulates mitochondrial protein pathway (TrkA/Erk1/2 Pathway) and neurotrophic response caused by glutamate-induced apoptosis; unregulated apoptosis leads to the quicker onset of neurodegenerative diseases. Improved PC12 cells in rats after receiving lion’s mane mushroom extract provides observation and possible enhancement of human neuronal function, nerve growth factor, and cholinergic nerves.

Lion’s mane mushroom works in regenerating damaged peripheral nervous system injuries, through Schwann cells and axons restoration. These results could benefit injured patients due to stroke and crashes. Without limitations to the study of lion’s mane mushroom, the low-cost use provides neuroprotective effects by safely and systematically targeting neurodegenerative diseases and peripheral injuries by reaching the blood-brain barrier essentially better than other conventional prescription medication.

Conclusions

The evidence provided supports the notion that the lion’s mane mushroom is beneficial for neurological health. Through collected research studies, the active constituents alleviate endoplasmic reticulum stress caused by a number of disturbances, reduces menopausal symptoms, depression, anxiety, and indefinite complaints, can improve cholinergic function, prevent cognitive deficits and amyloid B(25-35) impairment and improve hippocampal function as well as promote neuroprotective activity in the TrkA/Erk1/2 pathway. With no known adverse effects, the lion’s mane mushroom can be used to prevent neurological disorders, such as Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, and improve peripheral nerve damage caused by crush injuries. The lion’s mane mushroom has been used throughout Eastern Asia for medicinal and culinary purposes with the knowledge of its bioactive capabilities for years, and it should be an option for patients who are in need of neuroprotective activity in the Western part of the world.  

References

ATCC. (2018). Neuro-2a (ATCC® CCL-131™). Retrieved from https://www.atcc.org/products/all/CCL-131.aspx

Banasik, J. L. & Copstead, L-E. C. (2019). Pathophysiology (6th ed.). St. Louis, MO: Elsevier Inc.

Brandalise, F., Cesaroni, V., Gregori, A., Repetti, M., Romano, C., Orrù, G., Botta, L., Girometta, C., Guglielminetti, M. L., Savino, E., … Rossi, P. (2017). Dietary Supplementation of Hericium erinaceus Increases Mossy Fiber-CA3 Hippocampal Neurotransmission and Recognition Memory in Wild-Type Mice. Evidence-based complementary and alternative medicine : eCAM, 2017, 3864340. doi:  [10.1155/2017/3864340]

Brennan, C. (2016). Mushroom Polysaccharides: Chemistry and Antiobesity, Antidiabetes, Anticancer, and Antibiotic Properties in Cells, Rodents, and Humans. Foods (Basel, Switzerland), 5(4), 80. doi:10.3390/foods5040080

Lin, J. H., Walter, P., & Yen, T. S. (2008). Endoplasmic reticulum stress in disease pathogenesis. Annual review of pathology, 3, 399-425.

Kann, O. & Kovacs, R. (2007). Mitochondria and neuronal activity. American Journal of Physiology, 292(2), 641-657. https://doi.org/10.1152/ajpcell.00222.2006

Mebratu, Y., & Tesfaigzi, Y. (2009). How ERK1/2 activation controls cell proliferation and cell death: Is subcellular localization the answer?. Cell cycle (Georgetown, Tex.), 8(8), 1168-75.

Millucci, L., Ghezzi, L., Bernardini, G. & Santucci, A. (2010). Conformations and Biological Activities of Amyloid Beta Peptide 25-35. Current Protein & Peptide Science, 11(1), 54-67. DOI : 10.2174/138920310790274626

Mori, K., Obara, Y., Moriya, T., Inatomi, S., & Nakahata, N. (2011). Effects of Hericium erinaceus on amyloid B(25-35) peptide-induced learning and memory deficits in mice. Biomedical Research, 32(1), 67-72. Retrieved from https://www.jstage.jst.go.jp/article/biomedres/32/1/32_1_67/_pdf/-char/en

Mu, Y., & Gage, F. H. (2011). Adult hippocampal neurogenesis and its role in Alzheimer’s disease. Molecular neurodegeneration, 6, 85. doi:10.1186/1750-1326-6-85

Nagano, M., Shimizu, K., Kondo, R., Hayashi, C., Sato, D., Kitagawa, K., & Ohnuki, K. (2010). Reduction of depression and anxiety by 4 weeks Hericium erinaceus intake. Biomedical Research, 31(4), 231-237. Retrieved from https://www.jstage.jst.go.jp/article/biomedres/31/4/31_4_231/_pdf/-char/en

Nerve Injury Team. (2018, January 16). A Guide to Axonotmesis: What is It and How is It Different to Other Nerve Injuries? Retrieved from https://nerve-injury.com/axonotmesis/

Nevell, L., Zhang, K., Aiello, A. E., Koenen, K., Galea, S., Soliven, R., Zhang, C., Wildman, D. E., … Uddin, M. (2014). Elevated systemic expression of ER stress related genes is associated with stress-related mental disorders in the Detroit Neighborhood Health Study. Psychoneuroendocrinology, 43, 62-70. doi:  [10.1016/j.psyneuen.2014.01.013]

Rajagopalan, S. (2011). Crush Injuries and the Crush Syndrome. Medical journal, Armed Forces India, 66(4), 317-20. doi:  [10.1016/S0377-1237(10)80007-3]

Raman, J., Lakshmanan, H., John, P., Zhijian, C., Periasamy, V., David, P., Naidu, M., & Sabaratnam, V. (2015). Neurite outgrowth stimulatory effects of myco­synthesized AuNPs from Hericium erinaceus (Bull.: Fr.) Pers. on pheochromocytoma (PC-12) cells. International Journal of Nanomedicine, 10(1), 5853-5863. https://doi.org/10.2147/IJN.S88371

Rupcic, Z., Rascher, M., Kanaki, S., Koster, R. W., Stadler, M., & Wittstein, K. (2018). Two New Cyathane Diterpenoids from Mycelial Cultures of the Medicinal Mushroom Hericium erinaceus and the Rare Species, Hericium flagellum. International Journal of Molecular Sciences, 19(3), 740. doi:10.3390/ijms19030740

Sabaratnam, V., Wong, K-H., Naidu, M., & David, R. P. (2013). Neuronal health – can culinary and medicinal mushrooms help?.Journal of traditional and complementary medicine, 3(1), 62-68. doi:  [10.4103/2225-4110.106549]

Spelman, K., Sutherland, E. & Bagade, A. (2017). Neurological Activity of Lion’s Mane (Hericium erinaceus). Journal of Restorative Medicine, 6(1), 19-26. Retrieved from https://restorativemedicine.org/journal/neurological-activity-lions-mane-hericium-erinaceus/

Ueda, K., Kodani, S., Kubo, M., Masuno, K., Sekiya, A., Nagai, K. & Kawagishi, H. (2009). Endoplasmic reticulum (ER) Stress-Suppressive Compounds from Scrap Cultivated Beds of the Mushroom Hericium erinaceus. Biosci. Biotechnol. Biochem., 73(8), 1908-1910. Retrieved from https://www.jstage.jst.go.jp/article/bbb/73/8/73_90279/_pdf/-char/en

Uren, R. T., & Turnley, A. M. (2014). Regulation of neurotrophin receptor (Trk) signaling: suppressor of cytokine signaling 2 (SOCS2) is a new player. Frontiers in molecular neuroscience, 7, 39. doi:10.3389/fnmol.2014.00039

Westerink, R. H., & Ewing, A. G. (2007). The PC12 cell as model for neurosecretion. Acta physiological (Oxford, England), 192(2), 273-85. doi:  [10.1111/j.1748-1716.2007.01805.x]

Wong, K. H., Naidu, M., David, P., Abdulla, M. A., Abdullah, N., Kuppusamy, U. R., & Sabaratnam, V. (2011). Peripheral Nerve Regeneration Following Crush Injury to Rat Peroneal Nerve by Aqueous Extract of Medicinal Mushroom Hericium erinaceus (Bull.: Fr) Pers. (Aphyllophoromycetideae). Evidence-based complementary and alternative medicine : eCAM, 2011, 580752

Xu, C., Bailly-Maitre, B., & Reed, J. C. (2005). Endoplasmic reticulum stress: cell life and death decisions. The Journal of clinical investigation, 115(10), 2656-64. doi:  [10.1172/JCI26373]

Zhang, C. C., Cao, C. Y., Kubo, M., Harada, K., Yan, X. T., Fukuyama, Y., & Gao, J. M. (2017). Chemical Constituents from Hericium erinaceus Promote Neuronal Survival and Potentiate Neurite Outgrowth via the TrkA/Erk1/2 Pathway. International journal of molecular sciences, 18(8), 1659. doi:10.3390/ijms18081659

Zhang, J., An, S., Hu, W., Teng, M., Wang, X., Qu, Y., Liu, Y., Yuan, Y., … Wang, D. (2016). The Neuroprotective Properties of Hericium erinaceus in Glutamate-Damaged Differentiated PC12 Cells and an Alzheimer’s Disease Mouse Model. International journal of molecular sciences, 17(11), 1810. doi:10.3390/ijms17111810