Eleutherococcus senticosus : Studies and effects *

Ginseng is one of the most popular herbal supplements in the world. It is a plant widely used in folk and traditional medicines for cardiovascular, immune, nervous and endocrine systems, and according to the researchers, it has the ability to increase the non-specific resistance state, which characterizes it as an adaptogenic substance. There are different species of ginseng, such as the American, Chinese, Korean and Japanese ginseng; the Korean species (Panax ginseng) is being used for thousands of years as a tonic, prophylactic and “restorative” agent, with powerful antioxidant properties. For a long time, its use was empirical, because people used to believe that it was a panacea that promoted longevity, with beneficial effects for the treatment of physical fatigues. Nowadays, the active components of Eleutherococcus senticosus are well described, however, there are no data on the quantity of a certain class of these secondary compounds produced in each species. Although the Eleutherococcus senticosus extract may contain several substances, including vitamins, minerals, cellulose, and ethanol, the substances responsible for inducing various physiological responses are the eleutherosides (in the root) and ciwujianosides (in the leaf). As Eleutherococcus senticosus receives great attention by showing that its active components can provide protection against oxidative stress, among other benefits, contributing to health and the prevention and treatment of diseases, such as diabetes, cancer, cardiovascular disease and inflammation. The purpose of this article is to describe the main, adverse and toxicological effects of Eleutherococcus senticosus recently related in the literature.


INTRODUCTION
Eleutherococcus senticosus, world widely known as Acanthopanax senticosus (Rupr.et Maxim), belongs to the Araliaceae plant family, as well as other types of ginseng (Latin name), a generic term given to all species of Panax [1].It is also known as Siberian or Russian ginseng, ciwujia, eleuthero, eleuthero ginseng, touch-me-not and devil's shrub [2,3].
Ginseng is one of the most popular herbal supplements in the world [2].It is a widely used plant in folk and traditional medicines for the cardiovascular, immune, nervous, and endocrine systems, and according to the researchers Brekhman & Dardymov (1969) [4], it has the ability to increase the non-specific resistance state, which characterizes it as an adaptogenic substance.
There are other species of ginseng, such as the American, Chinese, Korean and Japanese ginseng [5]; the Korean species (Panax ginseng) is being used for thousands of years as a tonic, prophylactic and "restorative" agent (3), with powerful antioxidant properties [6].For a long time, its use was empirical, because people used to believe it was a panacea that promoted longevity, with beneficial effects for the treatment of physical fatigue [7].
The use of Panax as a source of raw materials for pharmaceuticals was very expensive for many years [2,5].Therefore, a group of Russian researchers looked for alternatives, and after the discovery, many years later, at the end of 1950, Eleutherococcus senticosus (ES) was recognized as a new medicinal plant [2,3].Despite having been described only in 1950, Eleutherococcus senticosus is a plant used by the Chinese for over 2000 years.Some reports describe its use as a medicinal remedy for the treatment of infections, resistance to fatigue and for immunological improvement [8].
In 1982, Baranov [9] concluded that the chronic administration of Eleutherococcus senticosus was more advantageous when compared to Panax, because it does not cause arousal in patients.It has a more intense protective effect on the immune system; in addition, it does not lead to the development of a similar stress syndrome.The seasonality influences the effects of these two types of ginseng, but there is not much variation in Eleutherococcus senticosus (ES) [3].
ES was recently included in the European Pharmacopoeia as a medicine derived from plants and it is, therefore, suitable for use in traditional herbal medicines and associations [10].
The 1994 DSHEA (Dietary Supplement Health and Education Act) regulation allows a direct commercialization of ES as a supplement for consumption in the United States without the regulation of the FDA (Food and Drug Administration) [11].

ACTIVE COMPONENTS OF ELEUTHEROCOCCUS SENTICOSUS
The active components of Eleutherococcus senticosus, the eleutherosides, were initially coded from A to F [12], and years later, Hikino et al. (1986) [13] studied seven eleutherosides coded as A, B, C, D, E, F and G, and through acid hydrolysis of these components, obtained the formation of glycosides, such as rhamnose, arabinose, xylose, mannose, galactose and glucose.
Based on several studies by Wagner et al. (1994) [14], the ES components were rated as phenylpropanes, compounds, lignans, coumarins, polysaccharides and other compounds, such as oleanolic acid, aromatic oils and sugar [8].In an attempt to bring order to these chemicals compounds, ES was divided into two classes: 1. Triterpenoid saponins, which are glycosides of oleanolic acid (referred to as eleutherosides I, K, L and M), and 2. Phenylpropane derivatives (eleutherosides B, B1, D and E), which are mostly glycosylated [15].
The ES root extract is standardized in 0.6% to 0.8% of eleutherosides, depending on the extraction method of solids [16,17].
Unfortunately, there are no data on the quantity of a certain class of these secondary compounds produced in each species.These compounds include, but are not limited to, phenylpropanoids (siringina, caffeic acid, sinapyl alcohol, and coniferyl aldehyde), lignans (sesamin, syringaresinol and its glycoside), saponins (daucosterol, β-sitosterol, and hederasaponine-B), coumarins (isofraxidine and its glycoside) and vitamins (vitamin E and beta-carotene) [15].
Eleutherococcus not only synthesizes lignans, but also siringina, syringaresinol and sesamin; it produces and accumulates precursors of lignans, such as hydroxycinnamic caffeic acid and other intermediate compounds, as co-niferaldehyde.These precursors have shown a significant antioxidant activity [15].
Although the Eleutherococcus senticosus extract may contain several substances, including vitamins, minerals, cellulose and ethanol [14], the substances responsible for inducing various physiological responses are the eleutherosides (in the root) and ciwujianosides (in the leaf) [1].

MAIN EFFECTS OF ELEUTHEROCOCCUS SENTICOSUS
Eleutherococcus senticosus, as well as Panax ginseng, seems to have a stimulating effect on the metabolism of substrates, as it significantly alters the mobilization and utilization of carbohydrates and fatty acids.Since the metabolism of substrates is essential, different types of ginseng can have ergogenic effect [5].Table 1 shows several studies performed in humans, using a supplementation made from ES, among other types of ginseng.According to the studies, we may observe that the acute supplementation has no effect on physical performance, whereas chronic supplementation can provide significant changes in various biochemical parameters.Some studies, using the supplementation of Eleutherococcus senticosus, report an improvement in heart rate recovery after physical exercise, improvement of the lactate removal ability, greater ability to obtain energy from aerobic metabolism (by increasing the oxygen consumption and utilization of fatty acids as a source of energy) and, therefore, an improvement of the performance [3,8,[18][19][20].These authors believe that these improvements are due to the action of eleutherosides, responsible for inducing various physiological responses, which are present in the root of Eleutherococcus senticosus [1].
The extracts from different parts of ES have been considered good for health [21].The ES antioxidant effect is related to improvements in the treatment of diabetes, cancer and inflammatory state, in addition to their immunoregulatory and immunomodulatory property, and antimicrobial and antiviral activity [11].
The hypocholesterolemic activity of sesamin, β-sitosterol compounds and its glycoside β-sitosterol β-D-glucopyranoside can be explained by their participation in antioxidant reactions on LDL (low density lipoprotein), Table 1.Effects of some types of ginseng on physical performance in humans.
Increased aerobic capacity, reduced lactate production and heart rate.
Standardized extract of Panax ginseng containing 4% or 7% of ginsenosides, during 9 weeks.[29] Young men, n = 30, data collected-aerobic capacity Improved aerobic capacity, reduced lactate production and heart rate, there was no difference between 4% and 7% of the content of ginsenosides.
Improved O 2 uptake, maximum breathing capacity, vital capacity and forced expiratory volume, reduced lactate production and heart rate; no significant changes for serum LH, testosterone, and cortisol.
No significant difference on the running time to exhaustion, aerobic capacity, heart rate, VE, and RPE.
In the adult group, there was an improved performance in the Cooper test (12 min race), and in the young group there was no significant difference.
Improved O 2 uptake, forced expiratory volume, vital capacity, reaction time and heart rate.
Significant increase in VO 2 max, physical strength.
Significant increase in the production of work, significant differences in the lactate level.
There was no significant difference in maximal heart rate, VO 2 max, workload, RER.
There was no significant difference in VO 2 , workload, exercise time, lactate, levels of hematocrit, heart rate, RPE.
No significant difference in VO 2 , RER, RPE, rate, heart rate, level of lactate and glucose.
There was no significant difference in the supramaximal work of short duration.
Significant reduction in total cholesterol and LDL cholesterol levels, reduction of free fatty acids, triacylglycerol, blood glucose, and significant increase in peak VO 2 max.
Significant improvement in endurance, time to exhaustion, decrease in the mean arterial pressure and VO 2 .
Standardized extract of E. senticosus 800 mg/day, during 8 weeks.[20] Men in recreational cycling training, n = 9, data collected-aerobic capacity, maximum heart rate, VO 2 , RPE, RER, free fatty acids and glucose in the plasma.
Significant increase in peak VO 2 , heart rate and improvement in endurance time.The production of free fatty acids in the plasma was increased, and the glucose level decreased significantly (P < 0.05) in 30 min within 75% of peak VO 2 .
Acute supplementation did not affect any of the parameters analyzed in the study.
Korean ginseng extract, 20 g, mixed with 200 mL of water 3x/day, during 7 days before the test, and four days after the test.[51] Male college students, n = 18, data Collected-Exercise-induced muscle damage, inflammatory response, insulin sensitivity.
Significant decrease in creatine kinase and interleukin 6 in the group supplemented with ginseng, and a significant decrease in plasma insulin and glucose, suggesting reduced muscle damage and decreased inflammatory response, resulting in improvements in insulin sensitivity.Source: Adapted and updated from Barke & Morgan [2] and Bucci [52].
and also, the sesamin has a direct effect on cholesterol re-synthesis.β-sitosterol also has an important effect on the cholesterol structure, reducing its absorption (as demonstrated in humans) and the ability to reduce insulin concentrations, as well as and antioxidant effects regarding cancer.β-sitosterol also has anti-inflammatory and antipyretic activities [15].The antihyperglycaemic action of β-sitosterol and its glycoside can be explained by the competitive enzyme inhibition in glucose breakdown, but it does not end the possibilities for this property [15].
The study by Rhie and Won (2004) [22] demonstrated the potent effect on body weight gain of mice treated with ES, which was significantly reduced, besides demonstrating a significant reduction in the plasmatic cholesterol concentration.One hypothesis for this important effect in reducing weight could be explained by the action of ES on glucose and insulin metabolism [20], besides the effect of lower concentrations of corticosterone in rats [11,23].

ADVERSE EFFECTS OF ELEUTHEROCOCCUS SENTICOSUS
A case was reported on the use of Eleutherococus senticosus in a man who used digoxin and who had high plasmatic concentration (digoxin).When the supplemen-tation was interrupted, the plasmatic concentration decreased [24].Diabetics who use ES should monitor blood glucose concentrations, due to the hypoglycemic effects reported in animals [25].

TOXICOLOGICAL EFFECTS
The safety and efficacy of the ES supplement were evaluated on the activities of CYP2D6 of the cytochrome P450 and CYP3A4 [26], suggesting that the ES extract at a dose as it is usually recommended does not affect the metabolism of CYP2D6 and CYP3A4, and, therefore, it is not harmful to the health of individuals [11,27].

CONCLUSION
ES may receive great attention by showing that its active components can provide protection against oxidative stress, among other benefits, contributing to health and the prevention and treatment of diseases such as diabetes, cancer, cardiovascular disease and inflammations.However, the researches comprise mostly in vitro tests or animals tested in vivo in the laboratory, and the studies may not necessarily apply to humans.When they apply, there may be no reliable results due to factors such as diet, lifestyle, exercise and the administration of other drugs, and also the actual health of the participants.Nevertheless, it is expected that further controlled studies in humans are performed for a better understanding of the ES effects and its implementation, conferring it an economic importance, since it may help in the treatment of several diseases.