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Chemistry, pharmacology and medicinal property of Rhodiola rosea from the selection of traditional applications to the novel phytotherapy for the prevention and treatment of serious diseases

Rafie Hamidpour, Soheila Hamidpour, Mohsen Hamidpour, Mina Shahlari, Mahnaz Sohraby, Nooshin Shahlari, Roxanna Hamidpour

ABSTRACT Rhodiola rosea is a remarkable herb that has been a part of traditional medicine system in order to stimulate the nervous system, to protect the body against oxidative stress, free radical damage, inflammation, and virus infection. Rhodiola rosea is included among a class of plant derivatives called adaptogen, an agent that help the body adapt to various stressors. Adaptogens have been claimed to treat a wide variety of medical conditions, from fatigue to cancer. The studies on Rhodiola rosea have shown that the plant has anti-stress, anti-anxiety, anti-fatigue, and anti-depressant properties with no significant side effects. Rhodiola rosea has been considered in drug development because of its pharmacological activities throughout the world, especially in parts of Europe, Asia, and Russia. Rhodiola rosea has shown more efficiency and safety than pharmaceutical drugs for anxiety and depression, which typically can have side effects, such as digestive upset, mood and sleep disorders. This research paper, suggests that Rhodiola rosea, in addition to cure common disorders such as depression, binge eating, anorexia, generalized anxiety disorders, and physical and mental fatigue, might contribute to prevent, reduce and treat serious diseases such as Alzheimer’s disease, Parkinson’s disease, cardiovascular disease, diabetes, and cancer. The aim of our future research is to extract Rhodiola rosea in to the filtration equipment then by purification and extended quality control produce tablets for the animal trials.

International Journal of Case Reports and Images (IJCRI) International Journal of Case Reports and Images (IJCRI) is an international, peer reviewed, monthly, open access, online journal, publishing high-quality, articles in all areas of basic medical sciences and clinical specialties.

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CASERevie wREPORT Artic le Peer Reviewed OPEN| OPEN ACCESS ACCESS Chemistry, pharmacology and medicinal property of Rhodiola rosea from the selection of traditional applications to the novel phytotherapy for the prevention and treatment of serious diseases

Rafie Hamidpour, Soheila Hamidpour, Mohsen Hamidpour, Mina Shahlari, Mahnaz Sohraby, Nooshin Shahlari, Roxanna Hamidpour

Abstract pharmacological activities throughout the world, especially in parts of Europe, Asia, and Russia. Rhodiola rosea is a remarkable herb that has Rhodiola rosea has shown more efficiency and been a part of traditional medicine system in safety than pharmaceutical drugs for anxiety order to stimulate the nervous system, to protect and depression, which typically can have side the body against oxidative stress, free radical effects, such as digestive upset, mood and sleep damage, inflammation, and virus infection. disorders. This research paper, suggests that Rhodiola rosea is included among a class of plant Rhodiola rosea, in addition to cure common derivatives called adaptogen, an agent that help disorders such as depression, binge eating, the body adapt to various stressors. Adaptogens anorexia, generalized anxiety disorders, and have been claimed to treat a wide variety of physical and mental fatigue, might contribute to medical conditions, from fatigue to cancer. The prevent, reduce and treat serious diseases such studies on Rhodiola rosea have shown that as Alzheimer’s disease, Parkinson’s disease, the plant has anti-stress, anti-anxiety, anti- cardiovascular disease, diabetes, and cancer. fatigue, and anti-depressant properties with no The aim of our future research is to extract significant side effects. Rhodiola rosea has been Rhodiola rosea in to the filtration equipment considered in drug development because of its then by purification and extended quality control produce tablets for the animal trials. Rafie Hamidpour1, Soheila Hamidpour2, Mohsen Hamidpour3, Mina Shahlari4, Mahnaz Sohraby5, Nooshin Shahlari6, Keywords: Alzheimer’s disease, Anti-fatigue, An- Roxanna Hamidpour6 tidepressant, Cancer and memory enhancement Affiliations: 1President, Pars Bioscience, Leawood, Kansas, 2 United States; School of Medicine Department of Pathology How to cite this article University of Kansas City Missouri, Kansas City Missouri 3 United State; Department of Hematology and Blood Hamidpour R, Hamidpour S, Hamidpour M, banking- Faculty of Paramedical Sciences- Shahid Beheshti Shahlari M, Sohraby M, Shahlari N, Hamidpour R. University of Medical Sciences-Tehran-Iran; 4BA in Biology, Chemistry, pharmacology and medicinal property Pars Bioscience, Leawood, Kansas, United States; 5BA, Pars Bioscience, Leawood, Kansas, United States; 6Summer of Rhodiola rosea from the selection of traditional intern, Pars Bioscience, Leadwood, Kansas, United States. applications to the novel phytotherapy for the Corresponding Author: Dr. Rafie Hamidpour, Pars Bioscience prevention and treatment of serious diseases. Int J LLC 14109 Cambridge Lane, Leawood, Kansas 66224, Case Rep Images 2015;6(11):661–671. United States; Ph: (913) 432-0107; Fax: (913) 432-5708; Email: [email protected] doi:10.5348/ijcri-201458-RA-10013

Received: 07 March 2015 Accepted: 01 July 2015 Published: 01 November 2015

International Journal of Case Reports and Images, Vol. 6 No. 11, November 2015. ISSN – [0976-3198] Int J Case Rep Images 2015;6(11):661–671. Hamidpour et al. 662 www.ijcasereportsandimages.com

INTRODUCTION Chemical composition The phytochemical analysis of the Rhodiola species Rhodiola rosea, also known as golden root or has shown that the major beneficial components include Lignum rhodium is a perennial herbaceous plant in the salidroside and tyrosol, which are rich in the rhizomes Crassulaceae family which has been used as a natural [12]. The dried rhizomes contained 0.05% essential oil. medicine from ancient times. This perennial plant reaches Terpenes and volatile compound have been isolated a height of 30–70 cm with a thick rhizome and yellow, from Rhodiola rosea. As given in Table 1, Myrtenol fragrant flowers. It is a remarkable herb that is valued in (36.9%), trans-pinocarveol (16.1%), geraniol (12.7%), traditional medicine in Eastern and Northern Europe, cumin alcohol (12.1%), linalool (2.7%), perilla alcohol Asia, China, and Russia for its unique pharmacological (1.7%) and dihydrocumin alcohols (12.1%) are the most activity [1]. The plant has been categorized as an abundant volatiles detected in the oil [13]. Geraniol “adaptogen“ by Russian researchers due to its ability to and myrtenol are responsible for the rose like odor of elevate body resistance to physical, chemical or biological the plant. A total number of 140 chemical compounds stressors [2], treat fatigue, promote longevity, and were identified in R. rosea roots. The principal support cognition and mood wellbeing [3]. Rhodiola components are phenylpropanoids (rosavin, rosin, rosea (SHR-5 extract) has been indicated as an adaptogen and rosarin), Phenylethanoids (salidroside, ρ-tyrosol) in the situation of fatigue, poor mental performance and and a monoterpene (rosiridin) which are responsible Rhodiola rosea phytochemical extracts, depression [3]. for the pharmacological effects of R. rosea [13, 3]. are the source of important biological activities which is Rosiridin has attracted particular interest because of its used widely in the treatment of a wide range of diseases effect in depression and senile dementia. Rhodioloside like those of the nervous and cardiovascular systems (salidroside) active principles of the SHR-5 extract [2], Alzheimer’s [4] and Parkinson’s disease [5], cancer were found to have neuroprotective, cardioprotective The studies of [2], and inflammatory diseases [6]. and hepatoprotective activities and can be effective pharmacological activities of R. rosea have revealed its in the prevention of a number of disorders related to hepatoprotective [3] and Monoamine oxidase A (MAO-A) neuroendocrine and immune system [3]. Three rosavin inhibitory effects [7], in addition to the antiviral [8] and compounds (rosavin, rosin, and rosarin) which are unique antibacterial activities of this plant [9]. to R. rosea (the most used species of Rhodiola genus) Phenylethanoid (salidroside, ρ-tyrosol), might be responsible for antidepressant, anticancer, phenylpropanoid glycoside (rosarin, rosavin, rosin) and neurotropic, and hepatoprotective effects of this herb [3]. monoterpene (rosiridin) are responsible for the bioactivity of R. rosea [10] Salidroside, rosarin, rosavin, rosin, and ρ-tyrosol are the most critical plant constituents used for Antioxidative effect therapeutic activities [2]. Salidroside and ρ-tyrosol have The imbalance between reactive oxygen species (ROS) been found in all Rhodiola species but the other active generation and antioxidant defense mechanism causes glycosides: rosavin, rosin, and rosarin have not been oxidative damage to the proteins, membrane lipids and detected in other genus of Rhodiola species. The compound nucleic acids in the cells. The increased generation of ROS rosavins (rosavin, rosin, and rosarin) are the compound damages the mitochondria, the power house of the body, that contains the highest percent of R. rosea which was which account for reducing the ability of maintaining not identified in other species. The compound salidroside is the most biologically active compound which shares Table 1: Chemical Composition of oil of Rhodiolarosea many of its effects with rosavin [2]. The absence of adverse drug interactions and side effects associated with R. rosea Compound Percentage in the clinical trials, make it possible to be used as a safe Linalool 2.7 medication [3]. Rhodiola rosea also can be applied as an Octanol 13.6 adjuvant to enhance therapeutic effects of other medicines in a number of disorders such as chronic pneumonia, 6,6-dimethyl-bicyclo[3,1,1] 1.0 hept-2-ene-2-carboxaldehyde chronic tuberculosis, vascular dystonia, cancer (reduction of metastasis), and in reducing the debilitating effects of Trans-pinocarveol 16.1 radiotherapy and chemotherapy [11] (Figure 1). Myrtenol 36.9 Geraniol 12.7 Common names Myrtanol 1.0 Rhodiola rosea has numerous common names. Some Perilla alcohol 1.7 of the best known names include arctic root, golden root, Dihydrocumin alcohol 2.1 king’s crown, lignum rhodium, orpin rose, rose root, Sedum rhodiola, and SHR-5 extract. The term “arctic Cumin alcohol 12.1 root” is used as a general name. However, arctic root is Reference: “Chemical composition of the essential oil from actually a trademark name for the specific commercial rhizomes of Rhodiola rosea L. grown in Finland.” Journal of extract. Essential Oil Research 17.6 (2005): 628–629.

International Journal of Case Reports and Images, Vol. 6 No. 11, November 2015. ISSN – [0976-3198] Int J Case Rep Images 2015;6(11):661–671. Hamidpour et al. 663 www.ijcasereportsandimages.com

Figure 1: The aim of our future research is to extract Rhodiola rosea in to the filtration equipment then by purification and extended quality control produce tablets for the animal trials. energy at the cellular level and results in muscular atrophy defense mechanism. Salidroside can act as blood tonic and muscle fatigue, leading to the decreased performance supplement and adaptogen. Patients with anemic of an individual [14]. hypoxia can take advantage of SDS as an adjuvant for Antioxidants are natural substances that prevent or erythropoietin (EPO) or other erythropoiesis-stimulating delay some type of cell damages and protect the body agents. This compound also defends erythroblasts against against the oxidative stress and free radicals. Various oxidative stress through up-regulating the expression Rhodiola species have shown significant antioxidant of antioxidant molecules, glutathione peroxidase, and activities. Among the 28 different compounds identified thioredoxin, and it also nullifies ischemia-induced in R. rosea, P-tyrosol, salidroside, and five salidroside- cardiomyocyte death through suppressing ROS like glycoside (Rhodiolin, rosiridin, rosarin, rosavin, and overgeneration [17, 18]. rosin), possess strong antioxidant activities [15]. Polyphenols in R. rosea neutralize oxidative reactions, Effect on cancer cells which are induced by free radicals since they are Cancer is a class of diseases characterized by out- excellent donors of protons and electrons. In addition, of-control cell growth. Complete eradication of cancer polyphenols, due to their metal chelating properties, are without damage to the rest of the body is the goal of the able to decrease oxidative stresses, induced by transition treatment. Some plant extracts that indicate potential metals [16]. as an anticancer agent have shown to be useful for the Salidroside (SDS), a major component extracted from treatment or prevention of the cancer with minimal Rhodiola rosea, is a glucoside of tyrosol which possess a toxicity, and they act synergistically with cytostatic broad spectrum of pharmacological properties including to reduce their toxicity. Study showed that the use of strong antioxidant activity. Salidroside induces its R. rosea extract in combination with the antitumor antioxidant effects to the cells by preventing collection of agent cyclophosphamide increased the anti-tumor and intracellular ROS, restoring the impaired mitochondria antimetastatic efficacy of the drug [2, 19]. function and mitigating oxidative-stress-induced The results of investigation in vivo show that R. rosea apoptosis [17]. extract has cytotoxic effect on tumor cell line through its Production and detoxification of reactive oxygen major component, polyphenols [20]. The cytotoxicity species (ROS) are of major importance in regulation effect of polyphenols on tumor cells are induced by of erythropoiesis (formation of red blood cells). reaction oxygen species (ROS) mediated mechanisms. Salidroside plays an essential role in maintaining normal Polyphenols including tannins and gallic acids, induce erythropoiesis through the up-regulation of antioxidant apoptosis in tumor cells by increasing intracellular

International Journal of Case Reports and Images, Vol. 6 No. 11, November 2015. ISSN – [0976-3198] Int J Case Rep Images 2015;6(11):661–671. Hamidpour et al. 664 www.ijcasereportsandimages.com peroxides [20]. The results show that salidroside, a unraveling the AD mystery is discovering what causes component isolated from plants Rhodiola genus, causes the disease. It has been suggested that oxidative stress growth inhibition in several human cancer cell line and dysfunction of neurogenesis play important roles in concentration between 1 µg/ml and 32 µg/ml dose in pathogenesis of AD [26]. Amyloid beta (Aβ) peptide, dependently by induction of G1-phase and/or G2-phase the hallmark of Alzheimer’s disease induces an oxidative arrest [21]. A number of studies have investigated the damage to neurons and finally causes neurons death. inhibitory effect of salidroside on the growth of stomach Reduced levels of anti-oxidative activity have been adenocarcinoma cells, leukemia cells, and parotid observed in the specific regions of the central nervous carcinoma cells in vitro [22]. In a few studies performed system of AD patients. in China, was found that Salidroside could inhibit tumor- Now researchers are paying great efforts to find induced angiogenesis in mice [22]. potent natural antioxidant with neuroprotective Breast cancer is the most common cancer diagnosed in potentials. Salidroside, an active compound occurring woman in the United States. It develops by the mammary naturally in Rhodiola rosea L. is protective against (Aβ)- cell proliferation induced by estrogen. Resistance of induced oxidative stress by the induction of antioxidant estrogen receptor negative (ER-) tumors to anti-hormone enzymes, thioredoxin (Trx), heme oxygenase-1 (HO-1), therapy is the main concern in breast cancer treatment. and peroxiredoxin-1 (Prxl); the down regulation of pro- Investigations of the effects of salidroside on the breast apoptotic protein Bax and the up regulation of anticancer showed its inhibitory properties on human breast apoptotic BcL-X1. Pathophysiology of neurodegenerative cancer MDA-MB-231 cells. The result indicated that diseases such as AD has shown that Aβ is associated salidroside in concentration between 5 µm and 80 µm with ROS generation which leads to mitochondrial dose dependently induced cell-cycle arrest and apoptosis dysfunction, lipid peroxidation and apoptosis. Exposure cell death in ER-negative and ER-positive tumors in to ROS also inhibits neurogenesis, which is the onset of human breast cancer [23]. cognitive impairments and memory deficits. Salidroside Thyroid cancer is the most frequent endocrine could decrease the intracellular ROS level and restore the neoplasia and accounts for about 2% of cancer-related abnormal mitochondrial membrane potential (MMP). deaths. Management options for thyroid cancer The neuroprotective effect of Salidroside may offer long- include total or near total thyroidectomy, radioiodine term protection in the pathogenesis of AD [26, 27]. therapy and pharmacotherapy. These patients may have neuropsychological concerns such as depressive Adaptogenic and anti-fatigue effects moods or developed cardiovascular problems such as Adaptogens are unique group of herbal ingredients hypertension, electrocardiogram abnormalities, and which help strengthen the body’s response to stress, diastolic dysfunction. In numerous studies, R. rosea enhance its ability to cope with anxiety, and fight fatigue. has demonstrated CNS stimulating, neuro-protective, They have the unique ability to adapt their function cardio-protective and antidepressant effects [2]. Since according to the body’s specific needs and do not disturb most of these symptoms are in fact the clinical aspect bodily functions at normal levels. Rhodiola rosea is of hypothyroidism, Rhodiola rosea is recognized to aid known as a plant’s adaptogens because it possesses anti- in patient preparation during the hormone withdrawal fatigue and anti-stress activities that can increase mental period. Oxidative stress increases when thyroid and physical working performance against a background hormones are missing during hypothyroidism [24]. In of fatigue or stress [28]. The phenylpropanoid glycoside vitro experiments using human erythrocyte reveal that called salidroside; flavonoids, phenolic, polyphenolic, and supplementation with R. rosea extract can protect cells flavonolignans are thought to be the main components from oxidative injuries in dose-dependent manner [25]. of stress- protective and adaptogens of Rhodiola rosea. These findings have also been replicated in human. Other constituents isolated from R. rosea include Rhodiola rosea have potentially additional benefits rhodioniside, rhodioloside A-E, rhodiolin, rosin, rosavin, as an adaptogen that tends to be a regulator, having rosarin, rosiridin, rosiridol, rhodalgin, acetylrhodalgin, normalizing effects on the organism. Hypothyroidism and lotaustralin might also be responsible for stimulant can be considered as a stressor and then R. rosea as an of R. rosea or adaptogenic effects. Such compounds can adaptogen that could help the organism’s responding play an active role in increasing energy, stamina, strength [24]. and mental capacity required in fight to fight situation to help the body to adapt and resist physical, chemical, and Alzheimer’s Disease environmental stresses [28, 29]. Alzheimer’s disease (AD) is a progressive brain Clinical efficacy of adaptogens in behavioral and disorder characterized by the memory and cognitive mental disorder has been reviewed. It is now accepted impairments. Neuropathologically, AD is defined by the that adaptogens have shown anti-fatigue, anti- accumulation of amyloid plaques and neurofibrillary depressant, anxiolytic, nootropic, and CNS stimulating tangles in certain region of the brain which are important effects. Adaptogens do not possess any side effects of in memory and can cause the loss of synaptic connection conventional drugs such as addiction, tolerance and between cells. One of the most important parts of

International Journal of Case Reports and Images, Vol. 6 No. 11, November 2015. ISSN – [0976-3198] Int J Case Rep Images 2015;6(11):661–671. Hamidpour et al. 665 www.ijcasereportsandimages.com abuse potentials, or impair mental function, nor do they increased in the US and worldwide. The most common cause psychotic symptoms with long-term use [30]. reason for people to use complementary therapies Neuro-degenerative disorders characterized by the is that they want to avoid the common side-effects progressive loss of structure or function of neurons in the of prescription anti-depressant drugs. A few natural brain region involved in learning and memory. Rhodiola psychotropics have been more extensively examined in rosea as an adaptogen could induce a positive effect in well-designed, placebo-controlled, double-blind studies. neuro-degenerative disorders due to their inhibitory Rhodiola rosea is one of these second-tier natural effects on the formation of p-SAPK (phosphorylated products for mood disorders [33]. The standardized stress-activated protein kinase). Related data may be extract SHR-5 (3% rosavin and 0.8% salidroside) from considered to add further support to the hypothesis that R. rosea has a significant antidepressant activity in mild adaptogens have beneficial effect on mental performance to moderate depression. The symptoms evaluated were and cognitive function [28]. The key point of action emotional instability, decreased motivation, cognitive of adaptogens on stress appears to be related to the complains and susceptibility to stress [34]. Significant regulation of homeostasis via hypothalamic-pituitary- improvement in the overall symptom of depression and adrenal axis and regulation of molecular chaperones, mood deficiencies was observed in a 6-week monitoring stress-activated c-Jun, N-terminal protein kinase, fork study in Sweden, which R. rosea was given daily with a head box O transcription factor DAF-16, cortisol, nitric dosage of two tablets a day, each containing 170 mg of oxide (NO) and beta-endorphin [30]. The optimal the extract [34]. The role of serotonin, a monoamine corticosteroid level is required for efficient cognitive neurotransmitter, is usually known and associated with function. Significant changes (up or down) in circulating depression, however, serotonin also has some cognitive levels of corticosteroids have been accepted as the functions, including the enhancement of memory reason for cognitive impairment. Regulatory effects of R. and learning. Regulation of serotonin at synapses is a rosea on the basal level of salivary cortisol results in an major mechanism of action possibly contributing to improvement in cognitive function [3]. pharmacological antidepressants. Central and peripheral Rhodiola rosea combines well with other adaptogens serotonin levels decreases in patients with depression. and tonics in appropriate dosages. The herbal drug Monoamine oxidase type A has an important role in ADAPT-232 is based on the synergistic effect of the degradation of biogenic amines such as epinephrine, three most efficient adaptogen plants, Rhodiola rosea, norepinephrine, and serotonin. Monoamine oxidase Schisandra chinensis and Eleutherococcus senticosus in inhibitors (MAOls) prevent the breakdown of monoamine a fix combination. Administration of single and repeated neurotransmitters including serotonin and therefore doses of ADAPT-232 has been shown to increase physical increase the concentrations of neurotransmitter in the energy as well as mental performance and cognitive brain. MAOls therapy with synthetics drugs are known function [30]. ADAPT-232 significantly increases to interact negatively with other medications and even secretion and release of stress hormones, neuropeptide Y with food. Monoamine oxidase inhibitors can cause death (NPY) and Heat Shock Protein 72 (Hsp 72) which increase if they are taken in overdose extent. There is an evident tolerance and adaptation to stress. These pathways that R. rosea acts as monoamine oxidase inhibitors and contribute to the anti fatigue effect of ADPAT, increase influence the level and activity of biogenic monoamines the attention and improve the cognitive function [31]. such as serotonin, norepinephrine, and dopamine in Furthermore, a number of studies have investigated the nerve terminal. Rhodiola rosea inhibits the activity the effects of ADAP-232 on pneumonia patients. of the enzymes responsible for monoamine degradation Clearly, adjuvant therapy on pneumonia patients with (monoamine oxidase and catechol-0 methyl transferase) ADAPT-232 has a positive effect on the recovery of the [3, 7]. General anxiety disorder (GAD) is a common patients, by decreasing the duration of the acute phase of disorder that involves chronic worrying, nervousness the illness, increasing mental performance of the patients and tension. There are different types of medication for during the rehabilitation period and by improving their GAD, including antidepressants, Benzodiazepines, and quality of life [30]. serotonin reuptake inhibitors. Patients who do respond to conventional treatment often experience adverse side Anti-depressant and general anxiety effects that may interfere with their constancy. Rhodiola rosea is a safe and tolerable alternative medicine. Depression is a severe despondency and sadness Administration of R. rosea in a dosages of 2–3 capsules accompanied by a feeling of desperation and each containing 100–170 mg daily, approximate the inadequacy. The mechanism of depression is complex. perfect dose to gain beneficial effects [35]. The therapeutic effects of anti-depressants such as Tricyclic antidepressants (TCAs), Monoamine oxidase inhibitors (MAOLs) and Selective serotonin reuptake Anti-inflammatory and neuro-protective inhibitors (SSRIs) come with a number of side effects effect like psychomotor impairment and dependence liability In general, inflammation is a localized reaction of the [32]. The use of alternative medicine especially natural body tissues to infections, irritation, injuries, or disorders products for the treatment of mental disorders has been

International Journal of Case Reports and Images, Vol. 6 No. 11, November 2015. ISSN – [0976-3198] Int J Case Rep Images 2015;6(11):661–671. Hamidpour et al. 666 www.ijcasereportsandimages.com of the immune system which produce redness, warmth, digestive and autonomic nervous system. The flavonols swelling, and pain. As we age, the level of inflammatory Kaempferol, Herbacetin, Rhodiolin, Rhodionon and immune cytokines increases and we get vulnerable to a Rhodiosin were isolated from Rhodiola rosea. The number of inflammation-linked diseases, such as cancer, compounds showed neuraminidase inhibitory and anti- arthritis, muscle weakness, fatigue, sleep disorder, influenza virus activities. The in vitro anti-influenza virus Alzheimer’s and Parkinson’s disease. An enormous activities of flavonoids were evaluated using two influenza amount of researches have demonstrated the link between viral strains, H1N1 and H9N2, testing their ability to chronic low-level brain inflammation and elevated brain reduce virus-induced cytopathic effect (CPE) in MDCK, glutamate levels, which are a neurotransmitter normally Madin-Darby Canine Kidney Cells (virus tissue culture). involved in learning and memory. In some cases, Anti-influenza activity depends on the position and the glutamate can be an excitotoxin that involves in nerve-cell number of hydroxyl groups on the flavonoids backbone. death in various neurodegenerative disorder including Kaempferol showed the highest activity against two Alzheimer’s and Lou Gehrig’s disease. Glutamate not only influenza viruses, H1N1 and H9N2 with the half maximal influence amyloid β production (the cause of Alzheimer’s effective concentration (EC50) values of 30.2 and 18.5 disease), but also amyloid β can change the levels of µM [36]. glutamate in the brain which increase the vulnerability Coxsackievirus B3 (CVB3) is important human of cortical neurons to glutamate cytotoxicity. It has been pathogen that belongs to picornavirus family. CVB3 is shown in several studies that R. rosea could improve the most common cause of viral myocarditis, a serious inflammation and neurotoxicity in cortical neuronal cells. disease that can further leads to dilated cardiomyopathy Rhodiola rosea modulates the neuronal over action and and cardiac failure and also often induce pancreatitis endogenous anti-inflammatory [6]. and aseptic meningitis. Although a few vaccine have Microglia, a type of glial cell, act as the first and been reported to be effective in a murine CVB3-induced main form of active immune defense in the central myocarditis model, but there are no effective therapeutic nervous system (CNS), and thus this cell play a key role agents against CVB3 for the clinic up to now [37]. in the inflammatory reaction. Inflammatory process, Salidroside (p-hydroxyphenethyl-β-D-glucoside) which in the central nervous system leads to neuronal cell is extracted from R. rosea demonstrated antiviral activity death, and inflammatory response is mediated by the while not affecting the normal physiological function of activated microglia, which remove the damaged cell by the host cells [8]. Salidroside exhibited obvious antiviral phagocytosis. The chronic activation of microglia may activity in vitro and protected myocardial cells against in turn cause neuronal damage through the secretion of CVB3 infection. The antiviral activities of salidroside cytotoxic molecules such as proinflammatory cytokines against CVB3 may be related to modulating serum (interleukin-1ß (IL-1), IL-6 and TNF-a), proteases, superoxide dismutase (SOD), serum nitric oxide (NO), and reactive oxygen species (ROS), and nitric oxide serum catalase (CAT), and serum malondialdehyde (NO). Therefore, suppression of microglia-mediated (MDA) activities to protect heart muscle against the inflammation can appear to be the most promising option in harmful effect of free radicals. Also salidroside has the neurodegenerative disease therapy. Since overproduction ability to increase the hemoglobin capacity to carry of NO plays an important role in neuroinflammatory oxygen, which provides protection for the myocardial disease, the effect of the R. rosea on nitric oxide cells from hypoxemia [8]. Since salidroside also has production was investigated in lipopolysaccharide (LPS)- shown antiviral activities against CVB3 in vitro, the induced microglia cells. Rhodiola rosea has shown to findings have significant implications for a potential strongly inhibit NO production and the expression of therapeutic agent for treatment of viral myocarditis and Inducible nitric oxide synthase (iNOS), the key enzyme influenza virus infections which is worthy of further for NO in LPS-stimulated microglia cells [6]. future researches [8].

Antiviral activity Antidiabetic The influenza is an acute infections disease caused by The antidiabetic effects of dietary administration an RNA virus of the family orthomyxovirus. Influenza of Rhodiola-water extract on streptozotocin (STZ)- virus infects the epithelial cells of respiratory tract that induce diabetes rat model were investigated. The STZ causes acute pulmonary diseases. Influenza outbreak is a toxin with the ability to damage pancreatic beta usually occurs in winter, killing numerous people in cells, resulting in hypoinsulinemia and hyperglycemia pandemic years. The epidemic outbreaks of influenza are [38]. The study used STZ mice as a model because it is associated with influenza virus type A and B. Type C virus considered an appropriate model to assess mechanisms is associated with minor symptoms. Two neuraminidase of diabetes and evaluate potential therapies [39]. Three inhibitors have been approved by FDA (zanamivir, and days administration of Rhodiola-water extract in STZ- oseltamivir) to treat influenza virus infection. Both of diabetic rats resulted in an increase of glucose transporter these inhibitors are active against influenza virus A subtype 4(GLUT 4) in skeletal muscle and a reduction of and B, however, they have several toxic effects in the phosphoenolpyruvate carboxykinase in liver [38]. It has

International Journal of Case Reports and Images, Vol. 6 No. 11, November 2015. ISSN – [0976-3198] Int J Case Rep Images 2015;6(11):661–671. Hamidpour et al. 667 www.ijcasereportsandimages.com been reported that Rhodiola-water extract have a long- defense process repair the damage caused by the toxin and term blood glucose level control effect and improves also protect body against any additional stress. It can be hyperglycemia by an increase of beta-endorphin secretion hypothesized that the plants adaptogen like R. rosea act from adrenal gland to activate opioid µ-receptors to as a mild stressor leading to activate an adaptive response achieve the higher of GLUT 4 gene expression in STZ rats which protects the cells from stressful environments and model [38]. increase the life span. In this way, it can be mentioned Evidence in both experimental and clinical studies that adaptogen acts as hormetic agents. The findings of a shows that increased oxidative stress is the common study support the view that low doses of R. rosea extract pathogenic factor causing diabetic mellitus and its (10–25 µg/ml) works in a deliberate and systematic way complication. Diabetes is a chronic metabolic disorder in order to increase the stress resistance and lifespan characterized by hyperglycemia and the inability of of C. elegans between 10 and 20%, whereas the higher tissues to utilize glucose. Hyperglycemia and fluctuation doses tested (250µg/ml) of Rhodiola showed a life span in blood glucose generate oxidative stress through shortening of 15–25% [41]. overproduction of reactive oxygen species. Dietary R. rosea supplementation results in a significant reduction Cardio-protective effects on blood glucose and lipid peroxide, increased levels Hyperhomocysteinemia (high homocysteine level of glutathione, glutathione peroxide, catalase, and in the blood) is a major risk factor of cardiovascular superoxide dismutase (SOD) in the liver. Rhodiola rosea disease. An abnormal accumulation of homocysteine, extracts may be effective for correcting hyperglycemia an amino acid that is produced by human body due to and preventing diabetic complications [40]. Managing consuming meat, is related to various cardiovascular diabetes without any side effect is still a challenge. diseases such as coronary heart disease, stroke Therefore, it is worth more investigation in the and peripheral vascular disease (fatty deposits in antidiabetic activity of natural products such as R. rosea peripheral arteries). Homocysteine exert its adverse on human in the future. effect on endothelial function by increasing superoxide production and decreasing the activity of nitric oxide Lifespan increasing effects synthase. Homocysteine could be a starting point for the Recent studies on Drosophila melanogaster and development of atherosclerosis by disturbing vascular Caenorhabditis elegans have shown that bioactive permeability, damaging the inner lining of the arteries components of R. rosea, particularly salidroside and/ and promoting blood clots. Salidroside extracted from or rosavins, may have an effect on lifespan and improve Rhodiola protect rats aortas against homocysteine- health spans. The plant adaptogens can induce their induce impairment of endothelium by inhibiting NOX2- effects by different routes. Adaptogens can extend the dependent ROS overproduction. These results suggest lifespan by increasing an organism’s resistance against that salidroside significantly inhibit ROS overproduction the damaging effects of different stress conditions. associated with vascular dysfunction, a common The plants adaptogens such as R. rosea interfere with pathological process in hypertension and diabetes [17]. the localization of DAF-16, a fork head/winged-helix transcription factor. The Caenorhabditis elegans DAF- Effect on Binge eating and Anorexia 16 transcription factor is critical for diverse biological Binge eating (BE) and Anorexia nervosa are official processes specifically longevity and stress resistance. eating disorders. Binge eating appears to be characterized Rhodiola rosea induce translocation of the DNF-16 by extreme overeating without subsequent purging transcription factor from the cytoplasm into the nucleus. episodes, usually secretive, and filled with shame [43]. DAF-16 in the nucleus reprograms the transcriptional Topiramate or sibutramine are medications that have activities favoring the transcription of a large number of been suggested to reduce BE. However, their uses are genes involved in stress resistance and longevity [41]. associated with a variety of adverse side effects which Moreover, dietary conditions are another hypothesis causes serious problems, such as cardiovascular disorder for anti aging effect of Rhodiola rosea. The effect of and stroke. As a result they have been withdrawn from R. rosea supplement on the lifespan of fruit fly depends the market in many European countries. Since stress is on diet composition particularly on the protein-to- a key factor in BE, a reduction of stress response might carbohydrate ratio. Dietary compositions with the show an effective mechanism for the treatment of BE. protein-to-carbohydrate ratio less than 1 extends the Therefore, due to its anti-stress properties, the effect of lifespan by 15–21%, but diets with high protein-to- Salidroside, an active principle of the dry extract of carbohydrate ratio or high caloricity do not support the R. rosea, was evaluated for treatment of BE. Studies have beneficial action of R. rosea on longevity [42]. shown that Salidroside abolishes BE by suppressing the Hormesis is favorable biological responses to a low activation of hypothalamic-pituitary-adrenal (HPA) axis, dose stress-induced stimulation resulting in biologically leading to a reduction of serum corticosterone flowing beneficial effects on growth, reproduction and longevity. chronic treatment [1]. Hormesis activates defense systems of the body and the

International Journal of Case Reports and Images, Vol. 6 No. 11, November 2015. ISSN – [0976-3198] Int J Case Rep Images 2015;6(11):661–671. Hamidpour et al. 668 www.ijcasereportsandimages.com

Eating disorders are associated with stress responses rosea is safe, however it is important to consider that R. depending on the intensity of stress itself. Moderate rosea a strong adaptogenic and tonic herb might have an stressor stimulate eating while acute stressor which addictive effect with other substance exhibiting stimulant causes high levels of CRF (corticotrophin-releasing properties (such as caffeine) [46]. factors), induce anorexia. In particular, considerable Continuous daily use of R. rosea for days and months evidence suggests a role for endogenous brain CRF is followed by an interval with no supplementation system in appetite regulation and the cause of eating (three weeks “on” and one week “off”). This clinical disorder. At doses of 15 and 20 mg/kg, Rhodiola extract recommendation helps avoid possible side effects at significantly inhibits the anorexia effects of stress within higher dosages such as insomnia, irritability, dizziness, a 60 min after a single oral administration of R. rosea dry month, and allergy (unspecified) [35]. extract [44]. Therefore, the difference effects evoked by The most commonly used standardized extract has a R. rosea on eating behavior could be attributed to its minimum of 3% rosavin and 1% salidroside. The typical ability to modulate the activation of several components daily dose for chronic administration extracts range from of stress-response system rather than a direct effect on 100–170 mg per day when standardized for 2.6% rosavin. orexigenic or anorexigenic mechanisms [1]. Evidence on the safety and appropriateness of R. rosea supplementation during pregnancy and lactation has not Effect on Parkinson’s Disease been established [2]. Parkinson’s disease (PD) is a chronic and progressive disorder of the nervous system that affects movements Conclusions of the body and the symptoms continue and worsen over the time. Parkinson’s primarily affects neurons Rhodiola rosea, which is also known as the golden in the area of the brain called substantia nigra. Cells root, is one of the most studied Rhodiola species. As an within the substantia produce and release dopamine, adaptogen, many health benefits are related to Rhodiola a neurotransmitter that controls the movement and drug extracts due to their balancing and regulatory effects. balance. In patients suffering from Parkinson’s, the Significant antioxidant activities have been documented amount of dopamine produced in the brain decreases. The for various Rhodiola species extracts. In Russian and shaking or tremor may begin to interfere with the daily Chinese folk medicine, the plant is used for stimulating activities of the PD patients. As these symptoms become the nervous system and decreasing mental and more pronounced, patients may have difficulty walking, physical fatigue. It has been shown in pharmacological talking or performing other simple tasks. Although there investigations that, R. rosea possess antioxidant, anti- is no cure, there are treatment options such as medication aging, anti-cancer and anti-cardiovascular disease and surgery to control the symptoms [5]. properties. As a dietary supplement, numerous The new plant preparation phytomix-40 (PM-40) preparations of extracts are used worldwide including is developed for the treatment of Parkinson’s disease. teas, homeopathic preparations and tinctures as well Phytomix (PM-40) is a mixture of natural extracts as standardized extract. Rhodiola rosea has enormous of 40 medical plants, including extracts of R. rosea, traditional and pharmacological use in supporting mood Eleutherococcus, ginseng, and other adaptogens and cognitive function. with neuroprotective properties. Animal experiments Rhodiola rosea is a versatile, safe and easily accessible demonstrated that PM-40 had a low toxicity. The plant which offers resistance to the physical, chemical and neuroprotective plant adaptogen can be used in complex biological stressors without interacting with other food or therapy for the Parkinson’s disease for improving its drugs. The remarkable therapeutic effects of this plant in efficacy. Oral administration of 10% solution of PM-40 to prevention and treatment of variety of human diseases, mice with MPTP-induced Parkinson’s syndrome reduces makes this plant very valuable for further investigation in the severity of rigidity and increase motor activity the area of pharmaceutical industries. [45]. The preparation normalized immunobiological parameters in PD patients and relieved the clinical ********* symptom of the disease. The mechanism of action of PM- 40 contributes to the recovery of the dopamine synthesis Author Contributions by healing of damaged neurons. PM-40 can be used with Rafie Hamidpour – Substantial contributions to the combination of other standard antiparkinson drugs conception and design, Analysis and interpretation of in order to improve their clinical effects and minimize data, Revising it critically for important intellectual side effects of Parkinson’s medication [5]. content, Final approval of the version to be published Soheila Hamidpour – Analysis and interpretation of data, Overview of toxicological and safety data Revising it critically for important intellectual content, Through the doses administered in clinical trials, there Final approval of the version to be published is no report of serious side effects that could be attributed Mohsen Hamidpour – Analysis and interpretation of to the extract of Rhodiola rosea. The normal usage of R. data, Revising it critically for important intellectual

International Journal of Case Reports and Images, Vol. 6 No. 11, November 2015. ISSN – [0976-3198] Int J Case Rep Images 2015;6(11):661–671. Hamidpour et al. 669 www.ijcasereportsandimages.com content, Final approval of the version to be published from Rhodiola rosea L. against coxsackievirus B3. Mina Shahlari – Acquisition of data, Drafting the article, Phytomedicine 2009 Mar;16(2-3):146–55. Final approval of the version to be published 9. Ming DS, Hillhouse BJ, Guns ES, et al. Bioactive Mahnaz Sohraby – Acquisition of data, Drafting the compounds from Rhodiola rosea (Crassulaceae). Phytother Res 2005 Sep;19(9):740–3. article, Final approval of the version to be published 10. Ma CY, Tang J, Wang HX, Gu XH, Tao GJ. Simultaneous Nooshin Shahlari – Acquisition of data, Drafting the Determination of Six Active Compounds in Rhodiola article, Final approval of the version to be published L. by RP-LC. Chromatographia 2008;67(5):383–8. 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