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Research progress of antidepressant edible and medicinal fungi and their active ingredients

Date:2022-6-21 16:47:15   

Worldwide, nearly one billion people suffer from depression of varying degrees. As the global pandemic of COVID-19 continues, the number of people with mental health issues around the world is also increasing. Depression, which is accompanied by a series of abnormal emotions such as depression, anxiety, panic, etc., is one of the main causes of social problems such as self-harm, suicide and crime in adolescents and adults. At present, the existing antidepressant drugs on the market have some problems such as poor efficacy, easy recurrence, and strong adverse reactions. Therefore, it is necessary to develop new safe and effective antidepressant intervention strategies.


In China, the use of traditional Chinese medicine has a long history. Early studies have found some Chinese herbal medicines that have proven antidepressant effects in clinical trials, including saffron and Hypericum perforatum, but there are few studies on edible and medicinal fungi for antidepressant. The traditional edible and medicinal fungi in China include Ganoderma lucidum, Lentinula edodes, Ophiocordyceps sinensis and Poria cocos, etc., because of their wide sources, long history of consumption, and remarkable health effects, they have great research interests. develop potential.


In recent years, various biological activities of edible and medicinal fungi have been continuously discovered, and the antidepressant biological active ingredients contained in them have the advantages of multi-target, safety and mildness, and small side effects. A 12-year long-term population study in the United States found that people who ate mushrooms had a lower risk of depression. Due to the complex pathogenesis of depression, the antidepressant mechanism of edible and medicinal fungi is also relatively complex. Existing studies have shown that it mainly regulates monoamine neurotransmitters, immune cytokines, neurotrophic factors and protection of neurons, etc. way to achieve antidepressant effect. The author summarizes 3 categories based on different mechanisms, including improving the body's antioxidant capacity, regulating monoamine neurotransmitters and their receptors, and interacting with various mechanisms, a total of 12 edible and medicinal fungi with antidepressant effects and their activities. The research progress of ingredients is expected to provide reference for the development of edible and medicinal fungi-derived antidepressant drugs and functional foods.


Improve the body's antioxidant level


Depression occurs with a decrease in antioxidant levels and an upregulation of oxidative and nitrosative pathways, i.e., an imbalance between antioxidants and reactive oxygen species (ROS) or reactive nitrogen species (RNS). In dysregulated environments, accumulated ROS and RNS cause neurological damage through different mechanisms, such as neuroinflammation, induction of neurotoxic effects of ROS and RNS pathway byproducts, such as kynurenine, and oxidative stress injury. And this nerve damage, especially neuroinflammation, is an important feature of depression and may be one of the causes of depression.


Therefore, intake of antioxidant active substances can increase the body's antioxidant level, reduce depression-induced oxidative stress and inflammatory responses, and relieve nerve damage. Some edible and medicinal fungi with antioxidant activity, such as shiitake mushrooms and Pleurotus cornucopiae, reduce depression symptoms mainly by increasing the body's antioxidant levels.


Pleurotus cornucopiae


Pleurotus cornucopiae, also known as small oyster mushroom, belongs to the genus Pleurotus of the Polypore family of the order Agaric, and is a low-temperature edible fungus in the genus Pleurotus. Ergothioneine (ERGO) is an amino acid mainly found in macrofungi with antioxidant properties. ERGO is hydrophilic and membrane impermeable, but a specific carrier-mediated transport system, carnitine/organic cation transporters (OCTN1), was found in mouse brain neurons. Therefore, ERGO may pass through the blood-brain barrier, thereby participating in neuronal differentiation, and may contribute to the antioxidant response in the brain. Studies have shown that feeding mice with chemically synthesized ERGO and ERGO extracted from Pleurotus alba for 2 consecutive weeks increased the concentration of ERGO in the plasma and brain of mice, both of which can significantly reduce the forced swim test (forced swim test). , FST) and the immobility time in the tail suspension test (TST), indicating that ERGO is the main component of the antidepressant effect of Pleurotus alba. Orally administered ERGO was transported across the blood-brain barrier, and the level of doublecortin-positive cells was significantly increased, suggesting that the antidepressant effect of ERGO may be related to the promotion of neuronal differentiation.


Agaricus bisporus


Agaricus bisporus, also known as white mushrooms, mushrooms, and foreign mushrooms, belongs to the mushroom family Agaricus. It is rich in amino acids, polysaccharides, proteins, vitamins and other nutrients, and is the most consumed edible fungi in the world. The study found that glucogalactan (GA) extracted from the fresh fruiting body of Agaricus bisporus has a therapeutic effect on trimethyltin chloride (TMT)-induced neuropathy in rats. GA was able to significantly stimulate the production of neurotransmitters and NO in brain tissue and significantly reduce oxidative stress. The results show that GA can protect the nervous system and improve the brain, thereby relieving depression.


Agaricus blazei


Agaricus blazei, also known as Brazil mushroom, is an edible fungus with an almond fragrance and a crisp taste. In recent years, studies have found more pharmacological effects of Agaricus blazei, such as antioxidant, immunomodulatory, anti-inflammatory, antibacterial, anticancer, tumor growth inhibition, and liver protection with antidiabetic activity. In the maze test and social interaction test, oral administration of Agaricus blazei extract (A. blazei extract, AbSE) was found to have anxiolytic effects on ischemic anxiety, and oral administration of AbSE (4, 8, 10 mg·kg-1) to treat arterial occlusion Induced cerebral ischemic anxiety for 30 days, daily oral administration of AbSE showed anxiolytic effects through elevated plus maze test and social interaction test. Oral administration of AbSE significantly increased cerebral monoamine levels, increased plasma corticosterone levels and decreased oxidative stress in cerebral ischemia rats. The results suggest that AbSE can treat anxiety caused by cerebral ischemia/reperfusion by reducing the level of oxidative stress.


Modulate monoamine neurotransmitters and their receptors


Several studies have shown that decreased levels of the monoamine neurotransmitters 5-hydroxytryptamine (5-HT), dopamine (DA) and noradrenaline (NE) are one of the main causes of depression . In animal and clinical studies, reductions in NE, 5-HT, and DA have been identified as important biomarkers for depression. Monoamine neurotransmitter reuptake inhibitors, as antidepressants, inhibit the recovery of monoamine neurotransmitters and maintain a higher concentration of neurotransmitters, thereby antidepressant-like mood and behavior.


The antidepressant mechanisms of edible and medicinal fungi that regulate neurotransmitters and their receptors are mainly divided into two types. One is the structure containing similar monoamine neurotransmitters, such as the active ingredient color in P. eryngii. Amines directly act as neurotransmitter analogs; second, by regulating neurotransmitter receptors, limiting the recycling of monoamine neurotransmitters by receptors, indirectly leading to increased levels of neurotransmitters, including Marasmius androsaceus and Grifola frondosa. Both antidepressant mechanisms can ultimately achieve the purpose of increasing the concentration of monoamine neurotransmitters.


Marasmius androsaceus


Marasmius androsaceus is a traditional medicinal fungus in my country. In recent years, studies have found that exopolysaccharide polysaccharide of M. androsaceus (MEPS) extracted from Marasmius androsaceus has the function of antidepressant activity. MEPS was extracted by submerged fermentation and administered to mice continuously for 7 days. MEPS significantly reduced the immobility time in FST and TST, and increased the levels of monoamine transmitters in the hypothalamus, including dopamine, norepinephrine, and serotonin. and 5-hydroxyindole acetic acid (5-hydroxyindole acetic acid, 5-HIAA). Subsequently, in a chronic unpredictable mild stress (CUMS)-induced depression rat model, MEPS not only increased the level of monoamine transmitters, but also increased tyrosine hydroxylation in the CUMS mouse model the expression level of the enzyme. After further separation of the active components of exopolysaccharide, it was found that the component MEPS2 separated by DEAE-52 ion exchange column also has antidepressant effect, the mechanism may be to increase the synthesis and release of catecholamine, and the hydroxylation of tyrosine Enzymes, dopamine receptors and Ca2+ and calmodulin-dependent protein kinase II also play important roles in this process.


Pleurotus eryngii


Pleurotus eryngii, belonging to the family Agaricaceae, is a widely cultivated edible fungus in my country. Pleurotus eryngii contains various bioactive compounds such as β-1,3-glucan, lovastatin, ERGO and active peptide Eryngin, which have anti-tumor, antibacterial, antiviral and immunity-enhancing effects.


Depression-like behaviors and memory impairments in ovariectomized rats were alleviated after long-term daily administration of ethanolic extract of Pleurotus erythraea as assessed by FST and Morris water maze test. The increase in synaptosome zinc content after oophorectomy was inhibited by Pleurotus erythraea extract, whereas zinc in synaptic vesicles is important for memory function and is associated with the development of depression. After XAD-16 resin purification of the ethanolic extract of Pleurotus elegans, the molecular structure of the component with antidepressant function was identified by LC-MS as tryptamine, a neurotransmitter. In the radioisotope-labeled receptor binding assay, both the ethanolic extract of Pleurotus elegans and the fractions separated by HPLC had higher specific serotonin receptor binding activity.


maitake


Grifola frondosa, commonly known as "maitake", belongs to the genus Papillonia of the family Poromycetes of the order Basidiomycetes, the order of Hymenophyta. Grifola frondosa is a traditional Chinese edible fungus with health and medicinal value. In "Shen Nong's Materia Medica", it is recorded that it has the effect of "reconciling the spleen and stomach, and calming the mind".


Bao Hongkun et al. injected mice intraperitoneally with Grifola protein β-glucan (GFPβG) at different doses (5, 8, 12.5 mg·kg-1), and mixed normal saline and imipramine (15 mg·kg-1). 1) Set as blank control and positive control, respectively, Grifola frondosa GFPβG significantly reduces immobility time in FST and TST, which is similar to the effect of positive drug imipramine. The β-glucan of Grifola frondosa can stimulate the expression of its receptor Dectin-1, and Dectin-1 further upregulates the downstream α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (amino- Levels of 3-hydroxyl-5-methyl-4-isoxazole-propionic acid, AMPA) receptor subunits p-GluA1 (S845), GluA1, GluA2 and GluA3. Using Dectin-1 inhibitor laminarin and AMPA specific inhibitor GYKI 52466 can block the antidepressant effect of GFPβG to further verify that the antidepressant mechanism of GFPβG is through the Dectin-1/AMPA receptor pathway. In terms of the sustained effect of drug efficacy, the level of the up-regulated AMPA receptor subunit p-GluA1 (S845)/GluA1 and the antidepressant effect can last for 3 days after the withdrawal of GFPβG.


Multiple mechanisms interact


In recent years, an increasing number of studies have found that depression is associated with immune activation and cytokines, including depression leading to inflammation, inflammation leading to depression, and a bidirectional relationship. Depression is clinically manifested as an increase in the level of inflammatory factors and a decrease in the level of anti-inflammatory factors, and antidepressant treatment can reverse this symptom, thus proposing the "inflammatory factor hypothesis" of depression.


Brain-derived neurotrophic factor (BDNF) is one of the major neurotrophic factors and plays an important role in the maintenance and survival of neurons and synaptic plasticity. The expression of BDNF is decreased in patients with depression, while the expression of BDNF is up-regulated by antidepressants, and the "neurotrophic factor hypothesis" of depression is proposed.


Because the mechanism of depression is complex and unclear, at present, the discovery of the relevant mechanism is mainly through the physiological and biochemical analysis of clinical depression patients, screening out the specific markers of depression, and then infering its role in the occurrence of depression. The mechanism of edible and medicinal fungi in antidepressant symptoms may include various mechanisms including anti-oxidative stress, regulation of cytokines, regulation of monoamine neurotransmitters and receptors, and regulation of neurotrophic factors.


Ganoderma lucidum


Ganoderma lucidum is the fruiting body of Polyporaceae fungi, and it is a medicinal and edible fungus with a history of medicinal use for thousands of years. As a precious Chinese medicinal material, the fruiting body, mycelium and spore powder of Ganoderma lucidum contain a variety of pharmacologically active ingredients.


Chinese medicine believes that Ganoderma lucidum is sweet and calm, and has the effect of calming the nerves. The water extract (100~400mg·kg-1) of Ganoderma lucidum mycelium was fed to mice, and the water extract was found to have anticonvulsant, antidepressant and anxiolytic effects through FST and elevated plus maze experiments. In addition, research has found that Ganoderma lucidum spore powder and Ganoderma lucidum spore oil have antidepressant effects. Ganoderma lucidum spore powder is obtained by breaking the spores ejected from Ganoderma lucidum during the growth and maturity period, and retains all the genetic material and health care effects of Ganoderma lucidum. Ganoderma lucidum spore powder can significantly alleviate the depression-like behavior of rats. The content of inflammatory factors (IL-6, TNF-α) in the serum of depressed rats treated with Ganoderma lucidum spore powder was significantly reduced, and the content of norepinephrine in the rat brain was significantly reduced. Decreased, the content of 5-HT increased, and could increase the expression of BDNF protein in the hippocampus of the depressed rat brain. Ganoderma lucidum spore oil is an oily lipid substance extracted from broken Ganoderma lucidum spores by supercritical extraction technology, which concentrates various active ingredients of Ganoderma lucidum spores. Ganoderma lucidum spore oil (850, 283, 141.5 mg·kg-1) was administered to mice with chronic mild unpredictable stimulation by gavage for 2 consecutive weeks. From the results of behavioral tests, Ganoderma lucidum spore oil had a significant antidepressant effect. And significantly reduce the content of glutamate in hippocampus. In addition, another study found that Ganoderma lucidum polysaccharides can resist adrenal ketone-induced neuronal apoptosis, indicating that it has neuroprotective effects.


Poria cocos


Poria cocos belongs to the dried sclerotia of Poria cocos, a fungus of the Polyporaceae family, and is a medicinal and edible fungus. It is mentioned in "Herbal Medicine" that it can "benefit the orifices to remove dampness, and improve the orifices to be happy and intellectual", and it is used as an important part of some antidepressant Chinese medicines such as Kaixin Powder and Xiaoyao Powder. The main biologically active components of Poria include triterpenoids, fatty acids, sterols and polysaccharides.


Poria cocos alcoholic extract achieves strong anti-inflammatory ability by inhibiting the NF-κB signaling pathway stimulated by lipopolysaccharide, and the anti-inflammatory ability can alleviate the inflammatory response caused by stress. Unpredictable chronic mild stress (UCMS) model rats were given the water extract of Poria cocos by gavage for 5 weeks. Increased and decreased levels of p38, NF-κB and TNF-α in the frontal cortex of UCMS rats. In the study of the antidepressant effect of Poria polysaccharide on the same UCMS rat model, Poria polysaccharide reduced the immobility time of forced swimming in UCMS rats, significantly improved the spatial learning and memory ability of rats, reduced hippocampal neuron damage, and increased AMPA. Expression and phosphorylation of receptor GluR1.


However, Xu Yan et al. [48] studied the effects of Poria cocos micro-powder (1.5 g·kg-1) and Poria polysaccharides (0.9 g·kg-1) on the depression-like behaviors of chronic unpredictable depression-stress model rats and found that, The antidepressant indexes of the Poria polysaccharide group were weaker than those of the Poria micropowder group. Therefore, the authors speculate that the simple polysaccharide of Poria cocos has no obvious effect on depression, but the various components of Poria cocos act together. In addition, recent studies have pointed out that the Poria cocos triterpenoid extract, the active ingredient of Poria cocos, also has antidepressant effects in the UCMS model. the level of the factor. Through further 16SrRNA gene sequencing and LC-MS metabolic analysis of gut microbiota, cecal content metabolomics found 13 biomarkers related to the antidepressant effect of Poria cocos There are strong correlations between groups, including primary bile acid biosynthesis, taurine and hypotaurine metabolism, and arginine and proline metabolism.


Shiitake mushrooms


Shiitake mushrooms are known as the second largest edible fungi in the world because of their thick, tender flesh and delicious taste. Mushroom polysaccharide (lentinan, LNT) is the main antidepressant component in Lentinus edodes. Sex glucan, has the effect of regulating the expression and activation of neurotransmitter receptors and reducing inflammation. Ma Qian et al. established an improved chronic unpredictable mild stress (CUMS) model, and administered the drug (2.5, 5.0 mg·kg-1) 1 hour before the modeling for 28 days. Results It showed that compared with the control group, the administration group of different doses of LNT could significantly alleviate the chronic stress response, reduce the inflammatory cytokines TNF-α and IL-6 in serum, and enhance the serotonin receptor 5 in the hippocampus of mice. -Expression of HT1A. Sun Lijuan studied the effect of LNT on antidepressant behavior in mice. Intraperitoneal injection of LNT can enhance the phosphorylation level of GluR1 S845 of the prefrontal AMPA receptor subunit in the mouse brain, thereby affecting the plasticity of AMPA synapses. The antidepressant mechanism of LNT is to increase the level of Dectin-1 receptors, thereby antidepressant-like behavior. In addition, in vitro cell experiments showed that LNT could also protect nerve cells from H2O2 oxidative damage.


Hericium erinaceus


Hericium erinaceus belongs to Polyporaceae, and is a traditional edible fungus in China. Hypoglycemic and hypolipidemic properties.


It has been found that Hericium erinaceus extract can promote hippocampal neurogenesis to achieve antidepressant and anxiety symptoms. Hericium erinaceus can also regulate the psychological problems of mood and sleep disturbances caused by obesity. Hericium erinone in Hericium erinaceus can stimulate the synthesis of nerve growth factor (NGF) through MEK/ERK and PI3K-Akt, and the occurrence of depression is related to the decrease of NGF secretion. Amycenone found from Hericium erinaceus can improve depression-like behavior in depressive mice induced by oral administration of lipopolysaccharide, and reduce the pro-inflammatory factor TNF-α and increase the anti-inflammatory factor IL-10 in their serum. In addition, ericin, which is rich in Hericium erinaceus, can reduce depressive behaviors caused by repeated restraint stress. The antidepressant mechanism and antidepressant active substances of Hericium erinaceus are diverse and complex, and further research is needed.


Cordyceps sinensis


Cordyceps, which is gradually formed by the invasion of insect pathogenic fungi into the body of insects. After the fungus invades, the insect body is filled with hyphae to form sclerotia, and the surface of the sclerotium is covered with a layer of hyphae and a sclerotium. Cordyceps. Among them, Cordyceps sinensis formed by Cordyceps sinensis is called Cordyceps sinensis.


Cordyceps sinensis is a precious medicinal fungus. Its main active ingredients include cordycepin, cordyceps polysaccharide, cordycepic acid, and cordyceps polypeptide. Studies have confirmed that cordyceps has anti-inflammatory, antioxidant, antitumor, antiviral, immune regulation and antidepressant properties. have significant effects. Among them, cordycepin is the main active ingredient of Cordyceps sinensis antidepressant. Cordycepin and fluoxetine (FLU, the positive control drug) were administered continuously for the last three weeks of the establishment of the CUMS mouse model. Behavioral tests showed that cordycepin played an antidepressant effect in the CUMS model. After biochemical analysis of the hippocampus, it was found that cordycepin increased serotonin (5-HT) and NE concentrations and decreased the levels of inflammatory factors TNF-α and IL-6. In addition, cordycepin may have a more rapid antidepressant effect than the antidepressant imipramine by modulating prefrontal AMPA receptor signaling. In addition, studies have found that some other cordyceps, such as Cordyceps militaris, also contain the antidepressant active ingredient of cordycepin.

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