Nerve growth factor (NGF) is considered as a very promising candidate in the treatment of Alzheimer’s disease [1]. However, NGF is a protein that becomes inactive after oral administration. A breakthrough in treatment occurred with the discovery of a class of compounds derived from the Lion’s Mane mushroom (Yamabush­itake, Hericium erinaceum), which stimulate the production of NGF [2,3].

Bioactive substances in H. erinaceum including hericenones, have the potential to repair neurological damage, improve brain function, and possibly prevent and treat Alzheimer’s disease. If the substances in H. erinaceum are able to cross the blood brain bar­rier, then NGF may act to repair neuronal function. Since early 1990s, Kawagishi and colleagues have been investigating the role of compounds derived from H. erinaceum in the treatment of de­mentia [4e6]. They found that H. erinaceum exhibited important bioactive properties, including the induction of NGF synthesis, in­hibition of the cytotoxicity of amyloid beta peptide, and protection against neuronal cell death caused by oxidative or endoplasmic stress.

Amyloban^®3399-a product made of amycenone, a standardized extract of H. erinaceum containing hericenones and amyloban is currently being tested for safety as a health food supplement. It has been reported that Amyloban^®3399 raises level of mental alertness, encourages positive behaviors, improves mood and attentiveness to one’s surroundings, and thus, should increase learning and motivation, while promoting voluntary interactions with others [7]. Carlsson et al. showed that one of the major problems of schizo­phrenia was the poor response of cognitive symptoms to available treatments, even when the positive symptoms showed improve­ments [8]. It has been repeatedly observed in clinical trials that positive symptoms may be reduced over a 4-12 week period, but it can take months to see improvements in cognitive symptoms. Based on these observations, it is hypothesized that Amyloban^®3399 may be beneficial for treating primary cognitive deficits and negative symptoms of schizophrenia.

Hericium erinaceum (HE; “Yamabushitake” in Japanese) is an edible mushroom that was named after the pom-poms worn by traditional warrior monks or the Yamabushi. HE has numerous multifunctional biological activities such as suppressing endo­plasmic reticulum stress, antioxidant activities, and stimulating nerve growth factor (NGF) synthesis. Several compounds extracted from HE exhibit neuro-protective activity in the brain [1234].

Our group previously reported 3 cases of mild neurocognitive disorders resulting from neuromedical treatments [5], which were successfully treated using H. erinaceum.

In this report, we describe an 86-year-old male patient with recurrent depressive disorder, who displayed mild cognitive impairment during antidepressant treatment with Mirtazapine. Mirtazapine was replaced HE extracts (Amyloban^Ⓡ3399). After 6 months, the cognitive function and body weight of the patient was restored, and he remains free from depression. Amyloban^Ⓡ3399 could be a useful antidepressant, particularly to treat geriatric depression, with no known adverse reactions.

Amycenone®, a proprietary extract developed from a mushroom called Lion’s Mane (Hericium erinaceus), has been awarded a patent in Japan.  Its patent in the U.S. is pending.

Amyloban®3399, a dietary supplement containing Amycenone® as an active ingredient, has been widely used and a number of clinical cases have also been reported for its role in certain conditions such as benign or mild dementia, snoring, sleep apnea, low quality of sleeping, juvenile apathy syndrome and schizophrenia.  Presentations on its clinical and laboratory studies have been made recently and a numbe r of articles on the original studies have been published on medical journals. The efficacy of the extract as introduced in such presentations and papers is persuasive as the active ingredients contained in the extract are explicitly identified and quantified, and the manufacturer has established the method of standardization to guarantee the actual content of these ingredients in their extract product.

Amycenone® has a patented ingredient that is confirmed to have an activity to increase the production of Nerve Growth Factor (NGF) in the brain as well as another ingredient to maintain healthy brain function by preventing nerve cell death by toxic amyloid β-peptide that is believed to be the cause of Alzheimer’s-type dementia. Furthermore, researchers are focusing on its potential activity of influencing the level of consciousness in the brain. Some promising results on the study may be coming soon.

So far, no significant adverse effects have been reported on the clinical uses of Amycenone®.

Medicinal Mushrooms  For OPTIMUM HEALTH AND LONGEVITY

 Ken Babal, C.N.

We all know that vitamin and mineral supplements can augment diets by providing essential nutrients that ward off disease. Likewise, botanicals can help us stay well, and can be used medicinally. There is yet a third category that ranks high for cultivating optimum health and resistance to disease. This is the mushroom category. Mushrooms are members of the fungal family, sometimes referred to as the third kingdom. Being neither plant nor animal, they possess highly unique characteristics that confer a wide array of health benefits.

In addition to essential nutrients, mushrooms contain many compounds with protective and therapeutic actions. Of particular interest is beta glucan, a complex carbohydrate, or polysaccharide that activates cellular immunity. Although we generally think of carbohydrates as providing energy, research reveals that some are involved in molecular recognition and cellular communication. Beta glucans are found in other foods, including oats and yeast. However, their chemical structures and effects are different from those of the beta glucans in mushrooms.

For thousands of years, mushrooms have been revered in China and Japan for their ability to maintain and improve health, preserve youth, and increase longevity. In many classic herbal formulations they are considered the main ingredient, or emperor. Today, there are hundreds of scientific studies validating the traditional usage of mushrooms. In numerous experiments and clinical trials, mushrooms have demonstrated antiallergenic, antibacterial, anti-inflammatory and antiviral actions, and an ability to sensitize cells to insulin.

There are a number of active ingredients in mushrooms that are obtained by alcohol extraction or methods other than simple hot water extraction.

The following are some examples of proven medicinal mushroom standardized extracts.

D-Fraction from Maitake  is perhaps the most famous of the mushroom extracts, having been the focus of much anticancer research. D-Fraction is a concentrated extract containing a protein-bound beta glucan, which has been shown to stimulate vital components of cellular immunity such as T cells, B cells, macrophages and natural killer (NK) cells.¹ Last year, a breakthrough study found that D-Fraction up-regulates twenty-two apoptosis genes, including the BAK-1 gene.² Researchers concluded that D-fraction has strong anti-cancer properties in breast cancer cells through BAK-1 gene expression. This is highly significant because it places D-fraction in a unique category apart from ordinary “immune boosters,” antioxidants and apoptosis-inducers.

Maitake is also the source of a unique glycoprotein called SX-Fraction, which has been shown to enhance insulin sensitivity. SX-Fraction is a completely different compound from D-Fraction, and was awarded a US patent in 2007 for anti-diabetic, anti-hypertensive, anti-obesity and anti-hyperlipidemic effects.³ Studies at Georgetown University found that SX-Fraction reduced levels of fasting blood glucose, blood pressure and body weight in genetically obese and diabetic rats. The extract also prevented hypertensive rats on a high sugar diet from developing insulin resistance. Furthermore, a clinical study found that Type 2 diabetics taking SX-Fraction for two months were able to significantly reduce their fasting blood glucose, triglycerides, insulin and body weight.⁴

Reishi is perhaps the most renowned of all medicinal mushrooms, and is prescribed as an anti-aging tonic. It is said to be a supreme “shen” (spiritual) tonic that invokes peacefulness and changes how we perceive life. Reishi is widely used in Asia to support cardiovascular functions and reduce LDL cholesterol. It has been found to be effective in preventing and treating arteriosclerosis, angina and shortness of breath associated with coronary heart disease.

Reishi contains steroid-like compounds (triterpenes) that inhibit inflammation and histamine, the chemical responsible for allergic symptoms. Medicinal triterpenes are fat-soluble and are concentrated by alcohol extraction.

Lion’s Mane is one of the edible mushrooms widely distributed in Japan and China.  Studies show that a class of compounds in Lion’s Mane, called hericenones, is able to regenerate neurons by stimulating production of Nerve Growth Factor.⁵ In addition, a fat-soluble fraction isolated from Lion’s Mane, called amyloban, is able to protect against neuronal cell death caused by toxic beta amyloid peptide, the main component of plaque that develops in the brains of Alzheimer’s disease patients.⁶

A study at a Chinese Pharmaceutical University compared Lion’s Mane extract with donepezil (Aricept), a common Alzheimer’s drug.⁷ Results showed that rats treated with the extract performed a water maze test equal to or better than those receiving the drug, depending on the dosage of the extract. Also, a double-blind, placebo-controlled study, demonstrated that Lion’s Mane is effective in patients diagnosed with mild cognitive impairment.⁸

And others mushrooms extracts are Agaricus, Cordyceps, Shiitake, Tremella, Meshima, Chaga, Coriolus and Poria. Agaricus enjoys superstar status in Japan. Its medicinal actions include counteracting or preventing tumors, fighting viruses, lowering cholesterol, regulating blood sugar levels and enhancing immunity. Cordyceps strengthens lung power and is a good choice for those who require energy for physical work or sports. It is considered one of the best sexual tonic. Shiitake is the most researched mushroom in the world, and is the source of two extensively studied derivatives used in Japan: lentinan and LEM. Tremella is a mushroom whose skin hydrating properties make it particularly useful as a beauty aid, both internally and externally. When compared to a form of hyaluronic acid, it demonstrated a stronger water holding capacity (500 hundred times its weight). Meshima mushroom has been attracting attention as being particularly protective of breast tissue. Researchers from Indiana University found that an extract of Meshima suppresses growth and invasive behavior of breast cancer cells.⁹ Chaga has received wide acclaim as a medicinal mushroom mentioned in the 1968 novel Cancer Ward. In Russian medicine, a tea made from Chaga is used as to treat ulcers and tuberculosis, and to counteract or prevent tumors. The immune-enhancing activities of Coriolus and its constituents have been extensively studied in Japan since the mid-1970s, with over 400 clinical studies conducted on it. It is the source of PSK (polysaccharide-K) (brand name Krestin), one of the all-time best-selling cancer drugs sold mainly in Europe and Japan. Poria is very popular in traditional Chinese formulations for tonifying the spleen and kidney and for clearing dampness.

References

1. Kodama, N. et al. “Effect of Maitake (Grifola frondosa) D-Fraction on the Activation of NK Cells in Cancer Patients,”  Journal of Medicinal Food 6 (4) 2003, pp. 371-377.

2. Soares, R. et al. “Maitake (D-Fraction) Mushroom Extract Induces Apoptosis in Breast Cancer Cells by BAK- 1 Gene Activation,” Journal of Medicinal Food XX(X) 2011, pp. 1-10.

3. US Patent No. 7,214,778 for “Glycoprotein with Anti-diabetic, Anti-hypertensive, Anti-obesity and Anti-hyperlipidemic Effects from Grifola Frondosa, and a Method for Preparing Same.” (2007)

4. Konno, S. et al “A possible hypoglycemic effect of maitake mushroom on type 2 diabetic patients.” Diabetic Med. 18, 2001.

5. Kawagishi, H and Zhuang, C. “Compounds for dementia from Hericium erinaceum.” Drugs of the Future, 2008, 33(2): 149-155.

6. Nagai, K. et al “Dilinoleoyl-phosphatidylethanolamine from Hericium erinaceum protects against ER stress-induced Neuro2a cell death via protein kinase C pathway.” J Nutr Biochem, 17 (2006) 525-530.

7. Kawagishi, H et al “Anti-dementia effects of a low polarity fraction extracted from Hericium erinaceum.” Abstracts of the 5^th  International Medicinal Mushroom Conference, p. 18-19, September 5^th – 8^th, 2009, Nantong, China.

8. Mori, K et al “Improving Effects of the Mushroom Yamabushitake (Hericium erinaceum) on Mild Cognitive Impairment: A Double-blind Placebo-controlled Clinical Trial.” Phytother Res, 23, 367-372 (2009).

9. Sliva D. et al “Phellinus Linteus Suppresses Growth, Angiogenesis, and Invasive Behavior of Breast Cancer Cells Through the Inhibition of AKT Signaling” British Journal of Cancer, 2008, pp. 1348-56.

Kawagishi and his group have studied compounds that are derived from medicinal mushrooms and their use in the treatment of dementia since 1991. They have found that H. erinaceum exerts important bioactivities, including the induction of nerve growth factor (NGF) synthesis, the inhibition of the cytotoxicity of beta-amyloid peptide, and the protection against neuronal cell death caused by oxidative or endoplasmic reticulum stress.

Since NGF was first discovered in the 1940s, it has garnered attention as a substance in the brain that curbs the degeneration and loss of neurons and that promotes the repair and regeneration of nerve function. However, NGF cannot pass through the bloodebrain barrier.

Amysenone (Amyloban^®3399, which contains a standardized extract of H. erinaceum) has been found to pass through the blood brain barrier, and its safety as a health food is currently being ascertained.

On the basis of the author’s first-hand experiences, Amyloban^®3399 was found to clearly increase alertness. The actions of Amyloban^®3399 in treating sleep-related breathing disorders were examined. Amyloban^®3399 was effective in improving sleep apnea and hypopnea syndrome.

The use of Amyloban^®3399 has been noted to result in the obvious restoration of cognitive function in mild cognitive disorder.

Compounds for dementia from Hericium erinaceum.  

Kawagishi, Hirokazu and Zhuang, Cun

Abstract

Our group has been conducting a search for com­pounds for dementia derived from medicinal mush­rooms since 1991. A series of benzyl alcohol deriva­tives (named hericenones C to H), as well as a series of diterpenoid derivatives (named erinacines A to I) were isolated from the mushroom Hericium erinaceum. These compounds significantly induced the synthesis of nerve growth factor (NGF) in vitro and in vivo. In a recent study, dilinoleoyl-phosphatidylethanolamine (DLPE) was isolated from the mushroom and was found to protect against neuronal cell death caused by β-amyloid peptide (Aβ) toxicity, endoplasmic reticulum (ER) stress and oxidative stress. Furthermore, the results of preliminary clinical trials showed that the mushroom was effective in patients with dementia in improving the Functional Independence Measure (FIM) score or retarding disease progression.