WHAT DOES CURRENT RESEARCH REVEAL ABOUT MUSHROOMS, THE NERVOUS SYSTEM, AND NEUROLOGICAL DISEASES?
The pumping of the heart, the inflation and deflation of the lungs, and the movement of our limbs are controlled by the nervous system. More complex than the control station at NASA, the nervous system is an intricate network of cells that coordinates all the actions in our body, including involuntary processes such as digestion. Neurons are the wiring of the nervous system, and they transmit information in the form of electrochemical impulses; every action in the body is stimulated by the electrochemical signaling of neurons. Our perception of the world is even created by neuronal signaling; change the wiring and our sense of the world is transformed. Alzheimer’s disease, bipolar disorder, depression, and memory loss are all directly correlated to improper functioning of the nervous system. Maintaining the nervous system’s ability to transmit information is crucial for our survival and general well-being.
Astrocytes are the most abundant cell in the brain. They maintain and repair neurons and regulate the internal environment of the nervous system. Among myriad roles, researchers have proclaimed the production of nerve growth factor (NGF) by astrocytes to be among the most important functions for maintaining brain health. NGF is a protein that binds to different receptors to activate the growth and repair of neurons. Researchers have found that NGF is critical for developing neuroplasticity, and low levels are associated with many neurological diseases. Neuroplasticity describes the brain’s ability to adapt to stimuli and to heal after injury; it is also crucial for memory retention and enhancing mood. Young kids are able to learn languages easily due to high levels of neuroplasticity; the neuronal networks in the brain literally change form to accommodate and store new information. A long bout of depression is difficult to overcome without structurally reorganizing neurons. In fact, two recent studies published in The American Journal of Geriatric Psychiatry and the World Journal of Biological Psychiatry have concluded that humans diagnosed with bipolar disorder and depression have reduced levels of NGF and therefore lack neuroplasticity.
Alzheimer’s disease is a neurological disease in which neurons become tangled and obstructed by a protein plaque known as beta-amyloid. In the late stages of Alzheimer’s, cognitive ability and memory are lost, and involuntary bodily processes begin to fail–remember that the nervous system controls every process in the body. The production of NGF and beta-amyloid proteins are controlled by the same pathway known as JNK. Proper functioning of the JNK pathway leads to neuronal regrowth and increased neuroplasticity, while a defective pathway results in improper folding of proteins associated with beta-amyloid formation. Because the JNK pathway is activated by different receptors, controlling receptor activity can have a significant effect downstream. Imagine the Colorado River that flows through the Grand Canyon in Arizona. The river is created by converging tributaries in Colorado. The larger Colorado River is the JNK pathway, and the tributaries are the different receptors. If the tributaries are dry, the Colorado will have a low flow, more exposed rocks, less turbidity, and an increased temperature. When the tributaries are full of snow-melt, the Colorado will flow strong and often muddy due to increased erosion. New rapids are formed, and the river is completely transformed. Depending on how the receptors are stimulated, JNK flows differently. Researchers have found that when NGF is not present or being synthesized, beta-amyloid is often being formed. Therefore, Alzheimer’s research has recently been centered around controlling JNK by using drugs that interact with upstream receptors.
Erinacines and hericenones are two types of compounds found in lion’s mane mushrooms that have a profound affect on the JNK pathway. According to a review published in the Journal of Mycology, the compounds in lion’s mane, and especially erinacines, promote the production of NGF. Research has implicated the consumption of lion’s mane with increased cognitive ability, neuroplasticity, and memory retention. Studies conducted both in vitro and in vivo have demonstrated that the enhanced brain activity is linked to the activation of JNK and the subsequent production of NGF. A study published in the Journal of Neuroscience Research has also shown that a drug similar to erinacines and hericenones has inhibited beta-amyloid formation through JNK expression. Therefore, some have proposed that lion’s mane may be an effective therapeutic for decreasing the progression of Alzheimer’s. The production of NGF by lion’s mane and the inherent benefits and effects of NGF is well researched. However, the nervous system is extremely complex and many mechanisms are not completely understood. More research is needed to conclude the extent of the effect of lion’s mane consumption on NGF production, inhibition of beta-amyloid synthesis, and its affect on neurological diseases.
Astrocytes: Cells in the brain and spinal cord that aid in many important processes. Among other things, they are responsible for maintaining nerve cells and optimizing metabolic conditions by controlling nutrients concentrations and pH.
Beta-amyloid: A short chain of amino-acids (small protein) that is formed through the fragmentation of a larger protein called amyloid precursor protein (APP). APP is thought to play a role in cell-signaling, and its fragmentation to beta-amyloid is theorized to be a contributing factor in the progression of Alzheimer’s disease.
Erinacines: A group of chemicals called diterpenoids that stimulate the production of nerve growth factor through the activation of the JNK pathway. The mycelium of lion’s mane is thought to have a larger concentration of erinacines than the fruiting bodies.
Hericenones: Terpenoids typically found in the fruiting bodies of lion’s mane. While it is thought that hericenones have brain enhancing properties, the mechanism is not as well understood as that of erinacines.
JNK: Also known as c-Jun N-terminal kinases, JNK is a pathway that when activated, modifies and releases proteins that may regulate cell growth, survival, and maintenance. JNK is controlled by upstream receptors.
Nerve Growth Factor (NGF): Is a protein that is extremely important for nerve growth and maintenance. NGF binds to and activates the different enzymes responsible for building nerve cells. Studies have shown that NGF is important for preventing and curing neurological diseases and even repairing the heart and brain after injury.
Nervous System: Coordinates all actions in the body. It is the control system. All of our senses are directed by the nervous system. Upon stimulus, electrochemical signals are circulated, and the body acts accordingly.
Neurons: Is a cell that receives and transmits information in the form of electrochemical signals. Like the wiring in an electronic device, neurons are how information is transferred in our body.
Neuroplasticity: The ability of neuronal pathways to change in accordance to external and internal stimuli. When our environment is changed, or the brain is injured, neurons are reorganized. Upon learning new information, neural pathways are changed to form what we call “memory.” Neuroplasticity is what enables us to remember information and heal after trauma.
Selected Research and Highlights:
Ma, B., Shen, J., Yu, H., Ruan, Y., Wu, T., & Zhao, X. (2010). Hericenones and erinacines: stimulators of nerve growth factor (NGF) biosynthesis in Hericium erinaceus. Mycology, 1(2), 92-98.
”Hericenones and erinacines are two natural products isolated from the fruiting body and mycelium of H. erinaceus, respectively, and most compounds exhibit the activity of promoting NGF synthesis. Hericenones and erinacines are low-molecular weight compounds that easily cross the blood–brain barrier.”
Mori, K., Obara, Y., Moriya, T., Inatomi, S., & Nakahata, N. (2011). Effects of Hericium erinaceus on amyloid β(25-35) peptide-induced learning and memory deficits in mice. Biomedical Research, 32(1), 67-72.
“It has been reported that H. erinaceus promotes nerve growth factor secretion in vitro and in vivo. Nerve growth factor is involved in maintaining and organizing cholinergic neurons in the central nervous system. These findings suggest that H. erinaceus may be appropriate for the prevention or treatment of dementia. In the present study, we examined the effects of H. erinaceus on amyloid β(25-35) peptide-induced learning and memory deficits in mice. Mice were administered 10 μg of amyloid β(25-35) peptide intracerebroventricularly on days 7 and 14, and fed a diet containing H. erinaceus over a 23-d experimental period. Memory and learning function was examined using behavioral pharmacological methods including the Y-maze test and the novelobject recognition test. The results revealed that H. erinaceus prevented impairments of spatial short-term and visual recognition memory induced by amyloid β(25-35) peptide. This finding indicates that H. erinaceus may be useful in the prevention of cognitive dysfunction.”
Mori, K., Inatomi, S., Ouchi, K., Azumi, Y., & Tuchida, T. (2009). Improving effects of the mushroom Yamabushitake (Hericium erinaceus) on mild cognitive impairment: a double-blind placebo-controlled clinical trial. Phytotherapy Research, 23(3), 367-372.
”A double-blind, parallel-group, placebo-controlled trial was performed on 50- to 80-year-old Japanese men and women diagnosed with mild cognitive impairment in order to examine the efficacy of oral administration of Yamabushitake (Hericium erinaceus), an edible mushroom, for improving cognitive impairment, using a cognitive function scale based on the Revised Hasegawa Dementia Scale (HDS-R). After 2 weeks of preliminary examination, 30 subjects were randomized into two 15-person groups, one of which was given Yamabushitake and the other given a placebo. The subjects of the Yamabushitake group took four 250 mg tablets containing 96% of Yamabushitake dry powder three times a day for 16 weeks. After termination of the intake, the subjects were observed for the next 4 weeks. At weeks 8, 12 and 16 of the trial, the Yamabushitake group showed significantly increased scores on the cognitive function scale compared with the placebo group. The Yamabushitake group’s scores increased with the duration of intake, but at week 4 after the termination of the 16 weeks intake, the scores decreased significantly. Laboratory tests showed no adverse effect of Yamabushitake. The results obtained in this study suggest that Yamabushitake is effective in improving mild cognitive impairment.”
Shimbo, M., Kawagishi, H., & Yokogoshi, H. (2005). Erinacine A increases catecholamine and nerve growth factor content in the central nervous system of rats. Nutrition Research, 25(6), 617-623.
“Nerve growth factor (NGF) is an essential protein for supporting growth and maintenance of peripheral sympathetic neurons. A novel diterpenoid erinacine, isolated from the cultured mycelia of Hericium erinacium, is known to have a potent stimulating effect on NGF synthesis.”
“Rats were treated with erinacine A by intubation for the first 3 weeks from birth to weaning and intragastrically from weeks 4 to 5. Rats treated with this compound had increased levels of both noradrenaline and homovanillic acid in the locus coeruleus (LC) at 4 weeks of age and increased levels of NGF in both LC and hippocampus at 5 weeks of age. The effects of erinacine A were confirmed in the central nervous system in rats.”
Calissano, P., Matrone, C., & Amadoro, G. (2010). Nerve growth factor as a paradigm of neurotrophins related to Alzheimer’s disease. Developmental Neurobiology, 70(5), 372-383.
“Recently, we have demonstrated a direct and causal correlation between interruption of the NGF signal and activation of amyloidogenesis. Upon NGF deprivation, differentiated PC12 cells show an intra and extracellular accumulation of Ab, followed by apoptotic death. Both these events are largely or completely prevented by Ab antibodies, b and c secretase inhibitors or partial silencing of APP mRNA (Matrone et al., 2008a). The evidence that serum deprivation induces apoptotic death which is not prevented by anti Ab agents suggests that the deficit of NGF supply may directly induce Ab-mediated apoptosis, probably through the activation of molecular mechanisms leading to an increase of APP expression and processing and/or to an unbalance of physiological secretase(s) activity.”
Yoshida, H., Metoki, N., Ishikawa, A., Imaizumi, T., Matsumiya, T., Tanji, K., et al. (2010). Edaravone improves the expression of nerve growth factor in human astrocytes subjected to hypoxia/reoxygenation. Neuroscience Research, 66(3), 284-289.
“In the present study, edaravone was found to activate the JNK pathway promoting NGF expression, which may be considered one of the mechanisms for pharmacological effectiveness of this agent. A recent study provided a similar finding for ethanol extracts of an edible mushroom, Hericium erinaceus (Yamabushitake), which was demonstrated to promote the NGF expression in 1321N1 human astrocytoma cells via JNK signaling.”
Yoshida, H., Itoh, K., Mimura, J., Satoh, K., Kosaka, K., Hayakari, R., et al. (2011). Edaravone and carnosic acid synergistically enhance the expression of nerve growth factor in human astrocytes under hypoxia/reoxygenation. Neuroscience Research, 69(4), 291-298.
“The production of NGF is considered to be one of the cardinal functions of astrocytes in maintaining homeostasis in the brain. Levels of brain and circulating NGF vary significantly in response to stressful events.”
Diniz, B., Teixeira, A., Machado-Vieira, R., Talib, L., Gattaz, W., & Forlenza, O. (2013). Reduced serum nerve growth factor in patients with late-life depression. The American journal of geriatric psychiatry: official journal of the American Association for Geriatric Psychiatry, 21(5), 493-496.
“NGF levels were significantly reduced in the elderly subjects with a previous history of major depression, in a similar fashion as found in patients presenting with a current depressive episode. This suggests that reduction in serum NGF levels may be a trait-dependent marker of LLD. The reduction in NGF levels observed in these subjects may indicate a significant disruption in neurotrophic regulatory mechanisms that take place during the depressive episode and do not completely recover despite clinical improvement after antidepressant treatment.”
Barbosa, I. G., Huguet, R. B., Neves, F. S., Reis, H. J., Bauer, M. E., Janka, Z., et al. (2011). Impaired nerve growth factor homeostasis in patients with bipolar disorder. World Journal of Biological Psychiatry, 12(3), 1-5.
“Plasma NGF concentrations were decreased in BD patients when compared to that seen with controls. BD individuals in mania had lower NGF levels than euthymic patients or controls. NGF levels were negatively correlated with the severity of mania. Conclusions. This is the first study to evaluate NGF levels in BD patients, providing further support to the hypothesis of impaired neuroplasticity in BD. These data also suggest that NGF measurement could be used for the biological marker for manic state.”
Kolotushkina, E., Moldavan, M., Voronin, K., & Skibo, G. (2003). The influence of Hericium erinaceus extract on myelination process in vitro. FiziolohichnyÄ zhurnal, 49(1), 38-45.
“The process of myelination in the presence of the extract began earlier as compared to controls and was characterised by a higher rate. Thus, extract of H. erinaceus promoted normal development of cultivated cerebellar cells and demonstrated a regulatory effect on the process of myelin genesis process in vitro.”
Mori, K., Obara, Y., Hirota, M., Azumi, Y., Kinugasa, S., Inatomi, S., et al. (2008). Nerve growth factor-inducing activity of Hericium erinaceus in 1321N1 human astrocytoma cells. Biological & Pharmaceutical Bulletin, 31(9), 1727-1732.
“Neurotrophic factors are essential to maintain and organize neurons functionally; thereby neurotrophic factor-like substances or their inducers are expected to be applied to the treatment of neurodegenerative diseases such as Alzheimer’s disease. In the present study, we firstly examined the effects of ethanol extracts of four edible mushrooms, Hericium erinaceus (Yamabushitake), Pleurotus eryngii (Eringi), Grifola frondosa (Maitake), and Agaricus blazei (Himematsutake), on nerve growth factor (NGF) gene expression in 1321N1 human astrocytoma cells. Among the four mushroom extracts, only H. erinaceus extract promoted NGF mRNA expression in a concentration-dependent manner.”
“In addition, H. erinaceus extracts induced phosphorylation of JNK and its downstream substrate c-Jun, and increased c-fos expression, suggesting that H. erinaceus promotes NGF gene expression via JNK signaling. Furthermore we examined the efficacy of H. erinaceus in vivo. ddY mice given feed containing 5% H. erinaceus dry powder for 7 d showed an increase in the level of NGF mRNA expression in the hippocampus.”
Meloni, M., Quaini, F., Emanueli, C., Madeddu, P., Campesi, I., Spillmann, F., et al. (2010). Nerve growth factor promotes cardiac repair following myocardial infarction. Circulation Research, 106(7), 1275-1284.
“Nerve growth factor (NGF) promotes angiogenesis and cardiomyocyte survival, which are both desirable for postinfarction myocardial healing.”
“NGF elicits pleiotropic beneficial actions in the post-MI heart. NGF should be considered as a candidate for therapeutic cardiac regeneration.”
 Diniz, B., Teixeira, A., Machado-Vieira, R., Talib, L., Gattaz, W., & Forlenza, O. (2013). Reduced serum nerve growth factor in patients with late-life depression. The American journal of geriatric psychiatry: official journal of the American Association for Geriatric Psychiatry, 21(5), 493-496.
 Barbosa, I. G., Huguet, R. B., Neves, F. S., Reis, H. J., Bauer, M. E., Janka, Z., et al. (2011). Impaired nerve growth factor homeostasis in patients with bipolar disorder. World Journal of Biological Psychiatry, 12(3), 1-5.
 Calissano, P., Matrone, C., & Amadoro, G. (2010). Nerve growth factor as a paradigm of neurotrophins related to Alzheimer’s disease. Developmental Neurobiology, 70(5), 372-383.
 Ma, B., Shen, J., Yu, H., Ruan, Y., Wu, T., & Zhao, X. (2010). Hericenones and erinacines: stimulators of nerve growth factor (NGF) biosynthesis in Hericium erinaceus. Mycology, 1(2), 92-98.
 Mori, K., Obara, Y., Moriya, T., Inatomi, S., & Nakahata, N. (2011). Effects of Hericium erinaceus on amyloid β(25-35) peptide-induced learning and memory deficits in mice. Biomedical Research, 32(1), 67-72.
 Mori, K., Inatomi, S., Ouchi, K., Azumi, Y., & Tuchida, T. (2009). Improving effects of the mushroom Yamabushitake (Hericium erinaceus) on mild cognitive impairment: a double-blind placebo-controlled clinical trial. Phytotherapy Research, 23(3), 367-372.
 Shimbo, M., Kawagishi, H., & Yokogoshi, H. (2005). Erinacine A increases catecholamine and nerve growth factor content in the central nervous system of rats. Nutrition Research, 25(6), 617-623.
 Mori, K., Obara, Y., Hirota, M., Azumi, Y., Kinugasa, S., Inatomi, S., et al. (2008). Nerve growth factor-inducing activity of Hericium erinaceus in 1321N1 human astrocytoma cells. Biological & Pharmaceutical Bulletin, 31(9), 1727-1732.
 Yoshida, H., Metoki, N., Ishikawa, A., Imaizumi, T., Matsumiya, T., Tanji, K., et al. (2010). Edaravone improves the expression of nerve growth factor in human astrocytes subjected to hypoxia/reoxygenation. Neuroscience Research, 66(3), 284-289.