Herbal Glossary : Fructus Schisandrae

Original plant of Fructus Schisandrae Dried Fruits Name Latin Name: Fructus Schisandrae
Common Name: Chinese magnoliavine fruit
Scientific Name: Schisandra chinensis (Turcz.) Baill.,
Schisandra sphenanthera Rehd. et Wils.
Chinese Name: 五味子
Pinyin Name: Wu wei zi Origin The dried mature fruit of Schisandra chinensis (Turcz.) Baill. or Schisandra sphenanthera Rehd. et Wils.; family Magnoliaceae. Where Does It Grow? Northern Wuweizi of specie Schisandra chinensis (Turcz.) Baill. is mainly produced in Jilin, Liaoning, Heilongjiang and Hebei provinces of China.

Southern Wuweizi of specie Schisandra sphenanthera Rehd. et Wils. is mainly produced in Hubei, Henan, Shaanxi, Shanxi, Gansu and Sichuang provinces of China. Nature and Taste It is sour and sweet in taste, warm in nature and manifests its therapeutic actions in the lung, heart and kidney meridians. Identified Active Components/ Major Chemical Constituents Northern Wuweizi (Schisandra chinensis) fruit contains 0.89% volatile oils. They include sesquicarene, 2-bisabolene、-chamigrene and a-ylangene. It also contains approximately 5% lignans. It contains 9.11% organic acids, which include citric acid, malic acid, tartaric acid, succinic acid and vitamin C. The seeds contain 33% fatty oil.

Lignans include schisandrin, and its derivatives -, -, -, -, -schisandrin, pseudo--schisandrin, deoxyschisandrin, neoschisandrin, schisandrol and others.

In addition to the above isolated lignan ingredients, the following lignan ingredients are also isolated. They include gomisins A, B, C, D, E, F, G, H, J, N, O, (-)-gomisin K1, (+)-gomisin K2, (+)-gomisin K3, (-)-gomisin L1, (-)-gomisin L2, (+)-gomisin M1, (+)-gomisin M2, epigomisin O, angeloylgomisin Q, angeloylgomisin P and tigloylgomisin P. The last two compounds are optical isomers.

Other compounds include citral, chlorophyll, sterols, vitamins C, E, resins, tannin and little amount of sugars.

Southern Wuweizi (Schisandra sphenanthera) contains active ingredients Schisandrin A, Schisantherin A, B, C, D, E and others. Historical Use

The Chinese name of Wuweizi (Fructus Schisandrae) is actually comprised of three Chinese words. The first word "Wu" (五) means "five". The second word "Wei" (味) means "taste", and the third word "Zi" (子) refers to "seed". As the name of the herb suggests, Fructus Schisandrae is a seed with five tastes, which are sour, bitter, sweet, pungent and salty. The Bencao Congxin (New Compilation of Materia Piedica) (Wu Yilo, 1757) stated, "Fructus Schisandrae is warm in properties. It contains all five tastes." The fruit skin is sweet, the fleshy tissue is sour and the seed core is bitter and pungent. All these parts have salty tastes. The predominant tastes of this herb, however, are sour and salty.

Historically, this herb has been used to:

astringe lung qi
nourish the kidneys' water
benefit qi (vital energy)
promote body fluid production
treat deficiencies by invigoration
benefit the eyes, relieve pupil dilation
astringe essence and strengthen yin
relieve heat and arrest sweating
stop vomiting and relieve diarrhea
relieve restlessness and thirst and remove edema (swelling)
treat alcoholic toxicity What is It Used for in TCM? Today, Fructus Schisandrae is used in Chinese medicine to astringe the lungs and nourish the kidneys. It helps produce body fluid, arrest sweating, consolidate essence and relieve diarrhea. It can also calm the heart and soothe the mind.
1. Treatment of deficiency type gasping caused by chronic cough.
The sour taste of Fructus Schisandrae makes the herb good at astringing. Coupled with its warm nature and moistening properties, Fructus Schisandrae astringes the lungs in the upper part of the body, and nourishes the kidney yin in the lower part of the body making it a herb used for treating the above syndrome.

(Please note that lungs rule the qi (vital energy). Normal respiratory functions depend on the lungs' qi dispersing and descending functions. When the cough becomes chronic, the continued upward and outward loss of qi during the cough will exhaust the qi contained in the lungs. The sour taste of Fructus Schisandrae can gather together the exhausted and dispersed qi, resuming the abundance of qi in the lungs. In TCM, it is known as the "astringing" of the lungs.) 2. Treatment of increased thirst syndrome caused by virtual heat and symptoms of dry mouth caused by body fluid exhaustion.
Coupled with the sour and sweet taste, Fructus Schisandrae benefits qi and helps produce body fluid to relieve certain symptoms arising from increased thirst syndromes and from dry mouth symptoms. 3. Treatment of spontaneous sweating and night sweating.
Fructus Schisandrae can astringe the lungs and arrest sweating. 4. Treatment of involuntary discharge of semen caused by kidney deficiency.
Fructus Schisandrae can invigorate the kidneys and astringe kidney essence, which helps with ejaculation control and involuntary discharge of semen. 5. Treatment of chronic diarrhea caused by deficiency type cold in the spleen and kidney.
Fructus Schisandrae can astringe the intestines and relieve chronic diarrhea. 6. Treatment of palpitations, insomnia and excessive dreaming caused by yin and blood deficiencies.
Fructus Schisandrae can invigorate the heart and kidneys and is good at calming the heart and soothing the spirit (Shen). It can also be selected as part of a herbal decoction to treat insomnia related to other causes. 7. Fructus Schisandrae powder for oral administration can also be used for transaminase (ALT and AST) elevations in chronic hepatitis. Pharmacological Actions
1. Liver Protective Effects Animal studies Protective effects on CCl4-induced liver damage: Rats were treated with 0.1% (v/v) tetrachloromethane (CCl4) in peanut oil 10ml/kg i.p. (intra-peritoneal injection) to induce liver damage. Six hours after administration, various crude extracts of Fructus Schisandrae, which are equivalent to 10g/kg raw herb, were administered to the rats by gavage once daily for four days. Liver damage was then increased by further injection of CCl4 six hours after the last dose of Fructus Schisandrae. Results showed that the ethanol extract of Fructus Schisandrae seed core had significant effects in lowering ALT (alanine aminotransferase). It also reduced histopathological damage of the liver. However, a Fructus Schisandrae ethanol extract from fleshy tissue and a water extract from the seed core showed no effects. Liver protective effects were thought to be related to active ingredients contained in the seed core, which were fat-soluble.

Protective effects in immunological liver damage: Liver damage induced by chemicals like CCl4 and thioacetamide is known as toxic hepatitis. This liver damage model can also be accomplished by immunological methods. Propionobacteria acnes (a gram-positive, non-sporing, anaerobic bacilli) was injected i.v. to mice tails to sensitize macrophages and Kupffer cells aggregated in the liver. After several days, lipopolysaccaride (bacteria toxin material) was injected i.v. into mice tails to activate the macrophages in the liver. As a result, a large amount of cytotoxic substances were released by the white blood cells causing liver damage.

This study showed that pretreatment with gomisin A (one of the active ingredients in Fructus Schisandrae) at a dose of 100mg/kg once daily for ten days had protective effects in the above immunological liver damage model. ALT (alanine aminotransferase) levels and mouse death rates were reduced as compared to controls.

In vitro studies
Protection for damaged liver cells: In vitro studies were done by extracting hepatocytes (liver cells) through collagenase perfusion. After liver damage induction on the liver cells by CCl4, both transaminase and lipid peroxidation product malondialdehyde (MDA) levels increased. Coagulation and liver cell membrane surface microvilli damage was observed. Pretreatment with 1mmol/L schizandrin B was shown to reduce various CCl4 induced damaging changes.

Inhibitory effects of CCl4 induced lipid peroxidation on liver microsomes and inhibitory effects on covalent binding between 14CCl4 and liver microsomal lipids and proteins: CCl4 induced liver cell damage is caused by CCl3, a free radical produced after liver cytochrome P450 activation. CCl3 is highly reactive and can induce covalent bonding with macromolecules such as lipids and proteins on biological membranes. As a result, the structure and functions of biological membranes such as the endoplasmic reticulum will be affected.

(i) In this in vitro study, rat liver microsomes (containing P450) were mixed with 0.1mg NADPH and 1mml of various ingredients of Fructus Schisandrae. The mixture was then warmed in a water bath at 37°C for 15 minutes. Afterwards, 10µl of diluted CCl4 (20-fold ethanol dilution) was added and warmed in a water bath for 30 minutes. The amount of malondialdehyde (MDA) produced was measured. Results showed that active ingredients of Fructus Schisandrae, which have protective effects in CCl4-induced liver damage, generally could inhibit the production of MDA as well.

(ii) Same procedures and methods were repeated with 14CCl4.14CCl4 that covalently bonded with liver microsomal lipids and proteins was extracted and its radioactivity was measured. Results were similar to the inhibitory effects in lipid peroxidation as reported in (i). Those active ingredients of Fructus Schisandrae, which had inhibitory effects in CCl4 induced liver lipid peroxidation, could also inhibit covalent bonding of 14CCl4 to liver microsomal lipids and proteins.
Clinical observation
In a clinical observation, capsule formulation of Fructus Schisandrae seed core oil extract was used to treat chronic active hepatitis. Each capsule contains 0.4g seed core oil, and the capsules were taken orally three capsules three times daily. One treatment period lasted for two months. thirty six cases were observed. The effectiveness in lowering ALT was reported to be 82.3%. 2. Liver Detoxification Effects Animal studies Effects on liver enzyme systems: Studies showed that when rats and mice were given oral administration of schisandrin A, schisandrin B, schisandrin C, schisandrol B and schisanhenol at a dose of 200mg/kg once daily for three days, there were increases in liver microsome cytochrome P-450, NADPH-P450-reductase, aminopyrine demethylatase, benzo(a,c)pyrene hydroxylase and hepatic microsomal proteins, which suggests enzyme activity for drug metabolism increases with administration of these active ingredients. Additionally, schisandrin B selectively induced P-450 activity in the in the smooth endoplasmic reticulum (ER) of liver cells.

Cell culture studies
Effects on liver enzyme systems: Rat liver microsomes treated with schisandrin B or schisandrol B were shown to increase the rate of metabolism of the carcinogen 3H-benzo (a, c) pyrene and the non-carcinogen 3H-estradiol. They accelerate transformation of carcinogen 3H-benzo(a,c)pyrene towards metabolic products with low carcinogenicity. They also antagonize the mutagenecity of carcinogen such as 3H-benzo(a,c)pyrene suggesting that certain ingredients contained in Fructus Schisandrae can enhance liver detoxification. 3. Protect Against Damage by Oxygen Free Radicals Oxygen free radicals refer to superoxide anions (O2-) and hydroxide free radicals (-OH). Too many oxygen free radicals produced in the cells will damage macromolecules such as nucleic acids, proteins, enzymes and biological membrane, leading to many adverse outcomes. Causes of certain diseases are associated with damage by oxygen free radicals. Examples include alcoholic hepatitis, inflammation, arthritis, reperfusion injuries following heart, brain or kidney ischemia, radiation injuries, aging and certain tumors.

Among the many tissue damage reactions caused by oxygen free radicals, lipid peroxidation of polyunsaturated fatty acids in biological membranes is the one of the most fundamental damage reactions. In light of the antagonistic effects shown by certain lignan ingredients in Fructus Schisandrae against CCl4-induced membrane lipid peroxidation of liver microsomes, these compounds may have similar antagonistic effects in membrane lipid peroxidation caused by oxygen free radicals. Animal studies Protective effect against peroxidation: An acute ethanol intoxication mouse model was employed to study the lipid peroxidation inhibitory effects of the ingredients of Fructus Schisandrae. Alcohol is known to cause liver damage. One of the reasons is that it may lead to liver lipid peroxidation. In the study, mice were given by mouth Fructus Schisandrae once daily for three days. At the last dose, mice were fasted for eight hours. Fifty percent alcohol was then administered by mouth at a dose of 15ml/kg, 12 hours later, MDA content in the liver tissue was measured. Results showed that after taking alcohol, MDA content in mice liver increased approximately two-fold. But when mice groups were pretreated with 0.5-1g alcohol crude extract, schisanhenol or 200mg/kg schisandrin B, the liver tissue MDA content measured was lower than the above control. Other active ingredients, Schisandrol A and B did not show significant lipid peroxidation inhibitory effects in vitro and also had no significant effects on the liver MDA elevation caused by acute alcohol intoxification. Therefore, the in-vivo and in-vitro study results were consistent.

Direct free radical scavenging effect: Using Electron Spinning Resonance (ESR), it was found that some active ingredients of Fructus Schisandrae, such as schisanhenol and schisandrin B and C, were able to scavenge O2- and -OH directly.

Promote the activity of anti-oxidative enzymes: In the cells, oxygen radicals generated are normally cleared by an oxygen radical scavenging enzymatic system. For instance, enzymes like superoxide dismutase (SOD), catalase and glutathione peroxidase (GSHPX) can scavenge O2-, -OH, H2O2 and LOO.

SOD O2- + O2- → O2 + H2O2 2H+ catalase H2O2 → O2 + 2H2O SOD 2H2O2 + RH → 2H2O + R GSH-PX ROOH + 2 GSH → ROH + GSSG + H2O
After rats were orally fed with 200mg/kg schisandrin B once a day for three consecutive days, cytosol SOD and catalase levels were significantly elevated. With more SOD and catalase activity, the body can clear up O2-,-OH and H2O2- more efficiently and thus alleviate damage caused by oxygen radicals.

Summarizing all of the above studies on oxidation, several ingredients of Fructus Schiandrae possess (1) O2-.and-OH scavenging effect (2) anti-H2O2 induced oxidative effects and (3) SOD and catalase activity promoting effects. 4. Effects on the Central Nervous System Animal studies Sedative effects: Animal experiments showed that schisandrols and its constituents, such as schisandrol A and schisandrol B, had tranquilizing-like effects on the central nervous system. In one study, rats were given i.p. injection of 60 or 120mg/kg schisandrol A. Fifiteen minutes later, either 50mg/kg of phenobarbital sodium or 180mg/kg of barbital sodium was injected. It was found that Schisandrol A had inhibitory effects on mice voluntary activities. As the dose increased, frequency of voluntary activities decreased.

Schisandrol A given by i.p. injection or by gavage feeding caused stupor in rats. The ED50 (effective dose) for i.p. injection was 107 (87-131.6) mg/kg, and the ED50 for oral dosing was 314 (340-420)mg/kg. Intra-ventricular injection of dopamine (5-45µg/kg) could antagonize the stupor caused by schisandrol A, but, injections of noradrenaline, 5-hydroxytryptamine (5-HT), acetylcholine (Ach), glycine or dopamine plus 5-HT could not antagonize the stupor caused by schisandrol A. This showed that the stupor causing effects of schisandrol A might be related to the dopaminergic system. 5. Effects on the Respiratory System Animal studies Excitatory effects: When normal, anaesthetized rabbits and anaesthetized dogs were given i.v. injection of Fructus Schisandrae decoction at dose groups of 0.1-0.5ml/kg and 0.5-1.0ml/kg, there were excitatory effects on the respiratory system. Both respiratory depth and rate increased. It also antagonized respiratory inhibition caused by morphine. When the acidity of the decoction was neutralized, the effects were slightly weakened. Tincture dosage forms also had similar actions. While there was excitation on respiration, blood pressure was depressed. Even after removing the vagus nerve and carotid sinus, respiratory excitation still existed. Therefore it was believed that the respiratory excitation was caused by direct stimulation of the respiratory center.

When rabbits were pretreated with Phenobarbital to induce respiratory inhibition, the i.v. injection of Fructus Schisandrae decoction at a dose of 0.5ml/kg could increase the respiratory frequency and amplitude and maintain regular respiratory rhythm.

Schisandrin at a dose of 5~10mg/kg had excitatory effects on respiration. On the other hand, when rats were given i.v. injection of gomisin at a dose of 5mg/kg, there was nearly no effects on respiration. 6. Toxicity When mice were administered by gavage with 5g/kg Fructus Schizandrae extract, seed suspension or fruit seed coat suspension for two days, no cases of death were reported, suggesting that Fructus Schizandrae is of low toxicity

Mice fed with 0.6 or 1.2g/kg Fructus Schizandrae ethanol extract once a day for ten days showed mild intoxification syndromes such as reduction in activities and erect hair. No change in hemogram and morphology of major organs was observed.

By Rec-assay, a hot water extract (90oC) of Fructus Schizandrae was able to induce mutation, while a warm water extract (45oC) was not .

Fifteen to sixty minutes after mice were fed by gavage with 10-15g/kg of lipid oil Fructus Schizandrae, symptoms such as breathing difficulty and activity reduction started to appear. After one to two days, cases of death were reported. Mice treated by gavage with 0.28g/kg volatile oil extract of Fructus Schizandrae experienced breathing difficulty and ataxia. All animals were found dead 1 to 3 hours later.

Schisandrin B was noted to be of lower toxicity. When ten mice were fed with a single dose of 2g/kg schisandrin B, no animal was found dead. When another 10 mice were gavage fed with 200mg/kg/day schisandrin B for 30 days, abnormalities in growth, major organs and hemoglobin levels were not observed. When schisandrin B was given to dogs, by gavage, once a day for four weeks, there were no detected changes in body weight, appetite, hemogram, liver tissues, and liver and kidney functions. Administration and Dosage A decoction is typically made with 3-6g of Fructus Schisandrae and boiled with three to four cups of water until the volume is reduced by half. A decoction is usually taken orally and split into two doses, but this dose, may taken all at once or escalated depending on the person's condition and recommendation by the Chinese medicine practitioner. Adverse Effect, Side Effects and Cautions It is contraindicated in individuals with unresolved influences of external evils or exogenous pathogens, internal presence of excessive heat, onset of cough and onset of measles.