Rhodiola What Does It Do?

Rhodiola rosea was named by the Greek botanist Linnaeus and is so called because its freshly cut rhizomes release a rose-like fragrance. It was first recorded in the book De Materia Medica. For centuries, Rhodiola Rosea has been used as a traditional medicine in Russia and the Scandinavian countries to enhance endurance, improve work efficiency, resist altitude sickness, fight fatigue, combat depression and mental illness. In China, Rhodiola Rosea has also been used for thousands of years, and its medicinal functions and efficacy are widely documented in various medical works [1–4].

There are more than 90 species of Rhodiola worldwide, mainly distributed in the Himalayas, North Korea, Japan and parts of North America. China is the main producing area of Rhodiola, and more than 70 species have been found in China. The species commonly used in North Korea and Japan are Rhodiola rosea L., Rhodiola sachalinensis A. Bor and Rhodiola crenulata H. Ohba, while Rhodiola rosea L. is mainly used in the United States and Europe. In China, Rhodiola crenulata is currently more widely used, and is mainly produced in high-altitude areas such as Tibet, Qinghai and Sichuan. Rose Rhodiola is mainly produced in Xinjiang. The main active ingredients in Rhodiola rosea are total rosavin, rhodioloside and tyrosol, while Rhodiola grandiflora only contains rhodioloside and tyrosol, and no total rosavin, so its efficacy is weaker than that of Rhodiola rosea [5].

1 The discovery of the active ingredients in Rhodiola Rosea Extract

The first country to carry out research on the standardization of Rhodiola Rosea was the former Soviet Union. In the 1970s, the Soviet Pharmacopoeia Commission approved the first generation of Rhodiola Rosea tincture products, with the active marker being salidroside and a content of not less than 0.8%. By the end of the 1980s, with the demand for rose rhodiola increasing significantly, a large number of fake wild rose rhodiola appeared on the market (other species of the genus Rhodiola contain salidroside). However, researchers found that even when the content of rhodiola extract in the fake wild rose rhodiola was high, the efficacy of the product could not reach the therapeutic level of wild rose rhodiola. They concluded that rhodiola should contain active substances with an undetermined structure, and that rhodioloside could not be used as the sole marker for the extract.

Based on this inference, Soviet scientists such as Kurlin conducted a large number of experiments and finally obtained evidence in 1986 that the chemical composition of Rhodiola rosea was different from that of other plants in the same genus. Rhodiola rosea contains special active ingredients called rosavin, rosarin and rosavin (collectively known as total rosavins, rosavins, Figure 1) [6]. There is a wealth of experimental evidence that Rosavins are only found in Rhodiola Rosea and have been identified as a marker for genetically pure Rhodiola Rosea and its extracts. Currently, the clinically used standardized compound of Rhodiola Rosea contains no less than 3% Rosavins and 0.8% to 1% Rosavin, with a ratio of 3:1.

As early as 1969, Rhodiola Rosea was listed as a legal medicine in the former Soviet Union, and the Pharmacology and Pharmacopoeia Commission of the former Soviet Union Ministry of Health approved the use of Rhodiola Rosea extract in medicine. In 1975, the 40% ethanol extract of Rhodiola Rosea with the approval code 75 /933/ 14 was approved for large-scale production as a medicine. The drug description describes it as a stimulant for physical weakness (fatigue), and it is used to treat various infectious diseases, mental and neurological diseases, and in healthy people to reduce fatigue, enhance memory, improve concentration and increase work efficiency (Figure 1) [7]. The usual dosage is 5 to 10 drops, 2 to 3 times a day, for 10 to 20 days, 15 to 30 minutes before meals. For mental illness accompanied by fatigue, the dose can be gradually increased from the initial 10 drops to 30 to 40 drops, 2 to 3 times a day, for a course of 1 to 2 months [8].

In 1985, the Swedish government officially recognized Rhodiola rosea as an anti-fatigue phytomedicine and included it in the textbook for training pharmacists, Textbook for Phytomedieine Pharmacist. The book describes the medicinal function of Rhodiola rosea as having an invigorating effect. In addition, the “pharmaceutical book” also describes rose rhodiola as one of the most commonly used stimulants in officially registered herbal products. In Denmark, rose rhodiola is also registered as a phytomedicine and is widely used as a stimulant to improve the efficiency of mental work under stressful conditions and as a tonic.

Rhodiola Rosea root extract is very low in toxicity, with an oral LD50 (lethal dose) of 28.6mL / kg or 3360mg / kg in rats, which is equivalent to 235g orally for a person weighing 70kg, so it has a huge safety margin. In the case of long-term medication, the usual clinical dosage of the extract is 360 to 600mg / d (1% rosavin content), 180 to 300 mg/d (2% rosavin content), and 100 to 170 mg/d (3.6% rosavin content). In emergency medication situations (such as exams, sports competitions, etc.), the amount of extract used is generally three times the dose for long-term medication [9]. Rhodiola rosea also has few side effects, and most users report that it improves their mood and physical performance and refreshes their spirits.

2 Adaptogen

In 1940, Soviet scientist Lazarev proposed the concept of “adaptogen” when studying the function of Rhodiola rosea [10]. It is a type of medicine that can enhance the body's nonspecific defense capabilities. It can neutralize adverse physical, chemical, and biological factors in the body by generating nonspecific resistance, and is the body's stress response to adapt to sudden changes in the internal and external environment. “Adaptogens” have the following three characteristics: (1) ‘Adaptogens’ act in a non-specific manner, resisting a broad spectrum of harmful stimuli (e.g., physical, chemical, or biological); (2) ‘Adaptogens’ have a balancing effect, counteracting or preventing disturbances caused to the body by external stressors; (3) ‘Adaptogens’ have no adverse effect on the body's normal functions.

With more than half a century of continuous development, the concept of “adaptogens” has also been continuously supplemented and improved [11]. The US Food and Drug Administration (FDA) defined “adaptogens” in 1998: “Adaptogens” are a new class of metabolic regulators that have been shown to increase an organism's environmental adaptability and ability to avoid external damage [12]. As a new concept, adaptogens have been widely recognized over the past decade or so and are widely used as functional terms. Table 1 lists the currently important medicinal plant species with adaptogen activity [13].

Rhodiola Rosea is one of the earliest adaptogens discovered and extensively studied. Research results show that Rhodiola Rosea, as an adaptogen, can enhance the body's resistance to various chemical, physical, and biological stressors [14]. It has been reported that the use of rose rhodiola extract can enhance the body's resistance to fatigue and improve concentration. The biological mechanism by which rose rhodiola, as an adaptogenic herb, can increase the activity of the central nervous system is that it can increase the expression level and activity of monoamine neurotransmitters and opioids [15].

Clinical trials have found that rose hip extract helps regulate cortisol secretion, relieve stress, and help insomnia patients relieve chronic fatigue syndrome [16]. In addition, after strenuous exercise, the large amount of reactive oxygen species (ROS) produced by the body can lead to increased blood oxygen consumption, resulting in fatigue and harmful symptoms. Rhodiola Rosea extract can effectively remove the reactive oxygen species produced during exercise, enhance the body's endurance during exercise, and relieve fatigue after strenuous exercise [17]. Phytoadaptogens can be broadly divided into three categories based on the chemical structure of their main active ingredients: phenolics/flavonoids, tetracyclic triterpenoids, and oxidized lipids. Rhodiolosides and total rosavin are both flavonoids and are the main active substances in Rhodiola rosea, playing an important role in the function of Rhodiola rosea as an adaptogen [18].

The concept of adaptogens is highly regarded in Europe and the United States, and its introduction has created many new business opportunities. Heavy workloads and high work pressure can increase anxiety and tension. People want to live a more relaxed life, and adaptogens can help people better relieve stress and emotions. Adaptogens also help to improve endurance and physical resilience. The trend in the market for adaptogens is to replace caffeine with energy-enhancing products, as excessive caffeine consumption can have a negative effect on health. There are already some plant-based alternatives to coffee, such as maté and guarana, but these plants also contain high levels of caffeine. As an adaptogenic herb, rose hip has a similar energy-boosting effect to caffeine without the negative side effects. Compared to central nervous system stimulants such as caffeine, the release of adaptogens is slow and long-lasting, which is fundamentally different from the stimulation caused by caffeine in the usual sense.

As shown in Figure 2 [19–21], stimulants can temporarily and significantly enhance the body's work capacity in a specific way, but this enhancement comes at the cost of disrupting the body's endocrine balance. After the effect of the stimulant wears off, the body's work capacity will quickly decline, accompanied by side effects such as headaches, weakness, and fatigue. In addition, long-term use of products containing stimulants can lead to a decrease in the secretion of catecholamines in the brain, which in turn causes a decrease in the stress response to stimulants. This in turn requires an increase in the amount of stimulants used to achieve the effect of improving work capacity, which is very harmful to human health. Adaptogens do not have these problems. They enhance the body's overall ability to work through a broad-spectrum, non-specific effect, without breaching the body's self-protection threshold for stress. After the effect of the medicine wears off, the body can continue to function normally. Adaptogens also replenish vital energy during the process of exciting the nervous system, thereby exerting an anti-fatigue effect.

3 Medicinal functions of the characteristic active ingredients of Rhodiola rosea

3. 1 Anti-fatigue and antidepressant activities

Chinese researchers have reported the anti-fatigue effect of Rosavin, an extract of Rhodiola rosea, on mice [22]. Using the forced swimming test as a model, the anti-fatigue activity of Rosavin at three different dosages (low, medium and high) was tested . The results showed that Rosavin can prolong the exhaustion swimming time of mice, maintain the glycogen and muscle glycogen content of mice after exercise, and reduce the levels of muscle lactate and blood uric acid in mice after exercise. The effect was most obvious at the high dose. Rosavin can increase glycogen reserves, remove accumulated lactic acid in the body, improve the body's glucose metabolism and reduce the proportion of protein energy. According to China's “Technical Regulations for the Inspection and Evaluation of Health Food”, it can be determined that Rosavin has the effect of relieving fatigue, and its mechanism of action is related to improving the body's material metabolism and improving the body's aerobic metabolic capacity.

Alexander et al. [23] evaluated the anti-fatigue effect of Rhodiola Rosea extract through a forced swimming test in BALB/c mice. The experiment found that the expression level of HSP72 in the serum of mice in the Rhodiola Rosea extract treatment group was significantly higher, and that the increase in the expression level of this protein could enhance the body's anti-fatigue ability. It can be seen that Rhodiola Rosea extract enhances the body's tolerance to fatigue by increasing HSP72 expression, thereby achieving the effect of anti-fatigue and improving mental state.

Panossian et al. [24] confirmed through experiments that total saponins and rhodiolosides have a synergistic effect in terms of antidepressant activity. In 2006, Kurkin et al. [25] reported the results of experiments on the antidepressant activity of Rosavin results. The researchers used the model to first test the antidepressant activity of extracts of Siberian ginseng, Rhodiola rosea, Echinacea purpurea and Schisandra chinensis, respectively, by using reserpine, clonidine and L-dopa to induce a mouse depression model. The results showed that Rhodiola rosea and Siberian ginseng extracts had a very significant antidepressant effect, and the effects of the two were similar, with the highest activity among all the test samples. By testing representative phenolic compounds in these extracts, it was found that Rosavin has a very significant antidepressant activity. Rosavin has a significant effect on preventing animal hypothermia and can significantly stimulate dopamine secretion. The possible mechanism of action is that Rosavin inhibits the activity of monoamine oxidase.

Borgonetti et al. [26] used a model of BV2 microglial cells stimulated by corticotropin-releasing hormone (CRH) to evaluate the anxiolytic activity of Rhodiola Rosea extract. The study found that Rhodiola Rosea extract (2.7% rosavin content) at a concentration of 20 μg/mL can eliminate the mental stress caused by CRH-induced neuroinflammation. The mechanism of action is to inhibit the nuclear translocation of NF-κB by regulating the activity of mitogen-activated protein kinase 2 (MAPK2), extracellular signal-regulated kinase 1/2 (ERK1/2), and c-Jun N-terminal kinase (JNK), thereby ultimately reducing the body's level of mental stress and achieving the effect of regulating the body's mental state.

3. 2 Antitumor activity

In 2008, Rozewska et al. [27] constructed a model by inoculating L-1 sarcoma cells of the same genotype into the skin of Balb/c mice to test the inhibitory effect of rosavin on tumor neovascularization in three different dose groups. The results showed that Rosavin had a significant inhibitory effect on the angiogenesis of tumor cells, especially in the high-dose group. The principle by which Rosavin inhibits tumor cell angiogenesis may be due to the action of its metabolite cinnamaldehyde in the animal body, as cinnamaldehyde has been found in previous studies to have inhibitory activity against tumor angiogenesis.

Studies have shown that the occurrence of bladder cancer is directly related to human aging, and Rhodiola Rosea extract has been proven to be an effective anti-aging “adaptogen” herb. A domestic research team discovered through experiments that Rhodiola Rosea extract can indeed be used as an anti-aging drug to significantly inhibit the growth of bladder cancer cells. Further research found that the Rhodiola Rosea extract components Rhodioloside and Rosavin have a significant inhibitory effect on bladder cancer T24 cells [28].

Lung fibrosis is currently difficult to cure clinically, has a high mortality rate and few treatment options, and is one of the causes of lung cancer. Recently, domestic researchers used a bleomycin-induced mouse lung fibrosis animal model to test the inhibitory activity of rosavin, a characteristic active ingredient in Rhodiola rosea, on lung fibrosis [29]. The results showed that rosavin can significantly improve the lung index and pathological state of bleomycin-induced lung fibrosis in mice. In addition, it was found that Rosavin can significantly reduce the expression of pro-inflammatory cytokines and reduce the infiltration of allergic cells into the lung homogenate. Further mechanistic studies found that Rosavin can downregulate the expression of hydroxyproline and malondialdehyde in lung tissue, increase the activity of superoxide dismutase and glutathione peroxidase, and ultimately increase the expression of Nrf2 (enhancing the body's chemical anti-cancer activity), while inhibiting the expression of NF-κB p65, TGF-β1 and α-SMA. The results of this study indicate that rosavin has good prospects for development as a treatment for pulmonary fibrosis.

Zhang et al. [30] established a rat model of bleomycin-induced pulmonary fibrosis and evaluated the protective effect of Rosavin on the lungs. The study found that Rosavin extract can alleviate the weight loss of rats caused by pulmonary fibrosis, reduce the content of hydroxyproline, and increase the content of glutathione and total superoxide dismutase. Enzyme-linked immunosorbent assay detected a significant decrease in the expression levels of tumor necrosis factor α (TNF-α), transforming growth factor β1 (TGF-β1), and interleukin 6 (IL-6) in the alveolar lavage fluid of modeling rats treated with rhodiola rosea extract by gavage. Matrix metalloproteinase 9 (MMP-9) and α-smooth muscle actin expression levels were significantly reduced, and there was a dose-dependent relationship with roselle extract. In addition, transforming growth factor β1 and matrix metalloproteinase inhibitor 1 expression levels in lung tissue were also reduced. The results showed that roselle extract can significantly alleviate the degree of pulmonary fibrosis in model rats.

3. 3 Improving immune activity

Studies have confirmed that T/B lymphocytes regulate the body's cellular/humoral immune response, respectively, and are the main effector cells of the adaptive immune system. Monocytes are also an integral part of the body's immune system, and they and the various cytokines they secrete are involved in multiple immune system processes. A domestic research team has experimentally observed that the main components of Rhodiola Rosea, rhodioloside, protocatechuic acid and rosavin, have a protective effect on the immune system of mice [31]. The results showed that rhodioloside not only promotes the conversion rate and proliferation rate of T/B lymphocytes at high concentrations, but also significantly enhances the phagocytic ability of peripheral blood leukocytes and abdominal cavity macrophages.

Rhodioloside has a wide range of immunological effects on the mouse immune system, and can participate in a variety of immune response reactions, but it also indicates that it is less specific. Rosavin, another main ingredient of Rhodiola, can specifically stimulate the proliferation and transformation of B lymphocytes, and its effect is higher than that of the positive drug group, which indicates that rosavin can specifically act on the humoral immune response system. Rosavin has a significant effect on promoting the transformation of resting T cells into progenitor cells. It can be inferred that the three active ingredients of Rhodiola rosea have the effect of promoting cellular and humoral immune functions. Different active ingredients can act on different immune target cells, providing a theoretical and experimental basis for further revealing the effects of Rhodiola rosea on the immune system.

Aron et al. [32] established a model of hydrogen peroxide-induced oxidative damage in mouse skeletal muscle cells (C2C12 cells) to evaluate the antioxidant capacity of rose rhodiola extract. The study found that after pretreatment with rose rhodiola extract, the expression level of HSP70 in cells exposed to hydrogen peroxide was the same as that in the blank group, but significantly lower than that in cells not treated with rose rhodiola extract. The results of the experiment show that Rhodiola Rosea extract can achieve its antioxidant activity by regulating the expression of the molecular chaperone HSP70.

3. 4 Anti-radiation activity

Domestic researchers have tested the anti-radiation damage activity of Rhodiola Rosea, Rosavin and Arbutin by constructing a radiation-induced intestinal injury model (RIII) in mice [33]. After the experiment, anatomized the mice to perform pathological tissue sectioning and an analysis of the viability of IEC-6 cells irradiated by radiation. It was found that all three compounds significantly increased the viability of IEC-6 cells irradiated by radiation, with Rosavin having the strongest activity. The experiment found that Rosavin can significantly improve the survival rate of mice and improve the damage to intestinal tissue in a radiation environment. The reason for Rosavin's effect is to improve IEC-6 cell viability by regulating allergic reactions and resisting external oxidative stress. This experiment confirms the prospect of Rosavin being developed into a drug for anti-radiation damage.

3. 5 Improves learning and memory

Researchers from the PLA General Hospital established a rat model of subacute aging induced by D-galactose and observed the effect of rosavin on improving the decline in learning and memory in rats [34]. The study found that rosavin can treat and reverse the decline in learning and memory caused by subacute aging at dosages of 12 mg/g and 24 mg/g, and that there is a dose-effect relationship. The study also found that the levels of cerebral blood oxygen PO2, O2 and SaO2 in senescent rats with improved learning and memory abilities after treatment with different doses of Rosavin increased to varying degrees, indicating that oral administration of Rosavin can effectively improve cerebral blood oxygen supply in senescent rats. Further studies have found that after treatment with different doses of Rosavin, the activity of antioxidant enzymes SOD, CAT and GSH-Px in the rat body rebounded significantly, while the accumulation of peroxidized substances MDA was significantly reduced. There is a quantitative-effect relationship, indicating that Rosavin's antioxidant mechanism is related to promoting blood circulation in rats, balancing the oxidation-reduction level in the body, and reducing oxidative damage.

Researchers from abroad have used the long-term potentiation (LTP) of synaptic transmission in hippocampal slices as a synaptic model of memory to evaluate the effect of rosavin, a characteristic active ingredient of Rhodiola rosea, on improving memory. The results showed that rosavin has a significant effect on enhancing memory, especially at high concentrations, and the effect is more pronounced when the drug is administered continuously [35].

4 Conclusion

Rhodiola Rosea is a natural herb with a variety of pharmacological activities. Rhodiola Rosea extract can effectively improve human immunity, regulate the central nervous system, cardiovascular system and endocrine system, and has various physiological functions such as anti-fatigue, anti-depression and anti-radiation damage. Current research on rose rhodiola is mainly focused on the medicinal functions of its extracts, with indications mainly including anti-fatigue, anti-depression, memory enhancement, exercise capacity enhancement, anti-tumor and anti-high altitude sickness. There has been relatively little research on the pharmacological activity of the functional monomers in the extracts (such as the characteristic ingredient total rosavin, which is specially introduced in this article).

References

[1] Li H J, Qiu L Q, Zeng F, et al. University Chemistry, 2019, 34 (9): 3743.

[2] Zhou S S, Jiang J G. Curr. Med. Chem., 2019, 26: 18331848.

[3] Zheng T, Bian F, Chen L, et al. Mol. Diagn. Therapy, 2019, 23(4): 489–498.

[4] Li X, Luo B Y. Int. J. Clin. Exp. Med., 2017, 10(12): 16499–16505.

[5 ] Wang Sunfu, Jin Li Si, Zheng Jingsheng. Haixia Pharmacy, 2017, 29 (2): 4347.

[6 ] Ganzera M, Yayla Y, Khan I, et al. Chem. Pharm. Bull. , 2001, 49(4): 465-467.

[7] Sharma P, Misra K. Edited by: Misra K, Sharma P, Bhardwaj A. Management of High Altitude Pathophysiology, Academic Press, Pittsburgh, 2019.

[8] Brown R P, Gerbarg P L, Ramaznov Z. HerbalGram, 2002, 56: 40–52.

[9] Kelly G S. Altern. Med. Rev. 2001, 6(3): 293–302. [10] Xiao Peigen. Medical Reference, 1972, 7: 30.

[11] Brekhman I, Dardymov I. Annu. Rev. Pharm., 1969, 9 (1): 419-430.

[12] Winslow L C, Kroll D J. Arc. Int. Med., 1998, 158(20): 2192-2199.

[13] Edited by: Porter R, Parker N. Bioactive compounds: Sources, properties and applications. Nova science publishers, New York, 2017.

[14] Chiang H M, Chen H C, Wu C S, et al. J. Food Drug Anal., 2015, 23: 359–369.

[15] Petkov V D, Yonkov D, Mosharoff A, et al. Acta Phy. Pharm. Bulg, 1986, 12: 3–16.

[16] Olsson E M, Scheele B, Panossian A G. Planta. Med. 2009, 75: 105–112.

[17] Xu J, Li Y. Mol. Med. Rep. 2012, 6: 1195–1198.

[18] Gupta P. J. Med. Plants Stud., 2019, 7(4): 278-281.

[19] Panossian A, Wikman G, Wagner H. Phytomedicine, 1999, 6: 287–300.

[20] Carlini E A. Pharmacol. Biochem. Be., 2003, 75: 501512.

[21]  Gulati  K ,Anand  R , Ray  A. Nutraceuticals  as  adaptogens : their role  in  health  and  disease / /Nutraceuticals. Academic Press,2016 : 193~205.

[22] Zhang Huiyun, Ma Zhaoyang, Wang Hongxin. Food Industry Science and Technology, 2013, 34(6): 357-359.

[23] Alexander P, Georg W, Punit K, et al. Phytomedicine, 2009, 16, 617-622.

[24] Panossian A, Nikoyan N, Ohanyan N. Phytomedicine, 2008, 15: 84-91.

[25] Kurkin V A, Dubishchev A V, Ezhkov V N, et al. Pharm. Chem. J., 2006, 40(11): 614-619.

[26] Borgonetti V, Governa P, Biagi M, et al. Phytomedicine, 2020, 68: 153143.

[27] Skopinska-Rozewska E, Hartwich M, Siwicki A K. Cent. Eur. J. Immunol., 2008, 33(3): 102-107.

[28] Liu Z B, Li X S, Simoneau A R, et al. Mol. Carcinogen, 2012, 51: 257–267.

[29] Xin X B, Yao D H, Zhang K. Biomed. Pharmcother. , 2019, 115: 108870.

[30] Zhang K, Si X P, Huang J, et al. Int. J. Mol. Sci., 2016, 17, 879.

[31] Chen W, Ma X Q, Fan W X, et al. Chinese Journal of Modern Applied Pharmacy, 2016, 33 (1): 38–42.

[32] Hernandez-Santana A, Perez-Lopez V, Zubeldia J M, et al. Phytother. Res., 2014, 28(4): 623-628.

[33] Zhou W J, Chen K Q, Lu Q. Chem. Biodivers., 2020, 17 (12): e2000652.

[34] Tan H L, Shi C, Lu J. Chinese Pharmacist, 2015, 18 (10): 17291732.

[35] Dimpfei W, Schombert L, Panossian A G. Front. Pharmacol. 2018; 9: 425.