952 Reviews Immunmodulatory and Antiproliferative Properties of Rhodiola Species* Authors Mari-Carmen Recio, Rosa-María Giner, Salvador Máñez Affiliation Department of Pharmacology, Faculty of Pharmacy, University of Valencia, Valencia, Spain Key words Abstract sponsible for many of the effects observed with l" Rhodiola ! Rhodiola extracts. l" salidroside The traditional medicines of Asia and Europe have The aim of this paper is to review the pharmaco- l" adaptatogen long used various Rhodiola species, which are en- logical effects not only of various Rhodiola species, l" antitumor demic to the subarctic areas of the northern mainly R. rosea along with Rhodiola imbricata, l" immunostimulant l" antioxidant hemisphere, as tonic, adaptogen, antidepressant, Rhodiola algida,andRhodiola crenulata, but also and anti-inflammatory drugs. In order to estab- of salidroside, focusing especially on its antioxi- lish the therapeutic uses of these plants in mod- dant, immunomodulatory, antitumoral, and anti- ern medicine, the pharmacological effects of Rho- proliferative activities, as well as to describe their diola sp. have been widely studied. Indeed, the therapeutic significance in disease management. most amply researched species, Rhodiola rosea, Although previous pharmacological studies have has been shown to possess antioxidant, adapto- established a scientific basis for possible thera- genic, antistress, antimicrobial, immunomodula- peutic uses of Rhodiola extracts and salidroside, tory, angiomodulatory, and antitumoral effects. high-quality, randomized, controlled clinical tri- Salidroside (p-hydroxyphenethyl-β-D-glucoside), als are still needed. a major compound in Rhodiola, seems to be re- Introduction as catechin and gallic acid) (l" Fig. 1) have been ! proposed as reference markers [1]. Rhodiola species are herbaceous perennial plants The roots and rhizomes of Rhodiola species have of the Crassulaceae family that have been used ex- been reported to contain distinct groups of chem- tensively in the traditional medicines of both Asia ical compounds. Initially, the compound responsi- received March 12, 2016 and Europe as tonic, adaptogen, antidepressant, ble for the unique pharmacological properties of revised April 11, 2016 and anti-inflammatory drugs. Rhodiola species these plants was believed to be salidroside, accepted April 12, 2016 grow in cooler regions in the subarctic areas of which, according to the Russian Pharmacopeia, This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. Bibliography the Northern hemisphere, including Northern constitutes 0.8% of the crude drug of Rhodiola ro- DOI http://dx.doi.org/ and Central Europe, Asia, and North America. It is sea L. However, subsequent studies have shown 10.1055/s-0042-107254 believed that the genus Rhodiola originates from that in addition to salidroside, rosin derivatives Published online May 25, 2016 the mountainous regions of Southwest China and are also important bioactive compounds. In fact, Planta Med 2016; 82: 952–960 the Himalayas [1]. Although the current taxo- the activity of R. rosea extracts was found to be © Georg Thieme Verlag KG Stuttgart · New York · nomic status of the genus Rhodiola is quite com- superior to that of the individual compounds, in- ISSN 0032‑0943 plex due to a generally similar morphology, a total dicating that the aforementioned glycosides are of 136 species have been identified according to probably not the only compounds responsible for Correspondence Prof. Dr. Mari-Carmen Recio GBIF [2]. From a chemotaxonomical point of view, the adaptogenic and immunostimulant proper- Department of Pharmacology eight compounds (the phenylpropanoids rosarin, ties of the plant. It is worth noting that the Faculty of Pharmacy rosavin, and rosin, the phenylethanoids salidro- R. rosea extracts used in most pharmacological University of Valencia Avda. Vicent Andrés Estellés s/n. side and tyrosol, the flavonol rhodionin, as well studies were standardized to contain a minimum 46100 Burjassot (Valencia) of 3% rosin and its derivatives and 0.8–1% salidro- Spain side in order to mimic the naturally occurring ra- Phone: + 34963543283 * Dedicated to Professor Dr. Dr. h.c. mult. Kurt Hostett- Fax:+3496344942 mann in recognition of his outstanding contribution to tio of these compounds in the R. rosea root, which [email protected] natural product research. is approximately 3:1. Recio MC et al. Immunmodulatory and Antiproliferative… Planta Med 2016; 82: 952–960 Reviews 953 Table 1 Distribution of Rhodiola sp. in relevant Holarctic areas [4,5]. China " Rhodiola alsia (Fröd.) S.H. Fu " R. atuntsuensis (Praeger) S. H. Fu " R. bupleuroides (Wall. ex Hook.f. & Thomson) S.H. Fu " R. coccinea (Royle) Borissova in Komarov " R. crenulata (J.D. Hooker & Thomson) H. Ohba " R. discolor (Franch.) S. H. Fu " R. dumulosa (Franch.) S.H. Fu " R. himalensis (D. Don) S.H. Fu " Fig. 1 Chemical structures of salidroside (1), rosavin (2), and rhodionin R. kirilowii (Regel) Maxim. " (3). R. macrocarpa (Praeger) S.H. Fu " R. primuloides (Franch.) S. H. Fu " R. purpureoviridis (Praeger) S.H. Fu " R. rosea L. " R. tangutica (Maxim.) S.H. Fu The demand for Rhodiola-based products has increased in the " R. tibetica (Hook.f. & Thomson) S.H. Fu past few years, necessitating a greater control over the quality of " R. wallichiana (Hook.) S.H. Fu the raw material supply and its collection from natural sources. " R. yunnanensis (Franch.) S. H. Fu " Studies have demonstrated that the content of salidroside as well Pakistan R. pachyclados (Aitch. & Hemsl.) H. Ohba " R. saxifragoides (Fröd.) H. Ohba as that of rosin and its derivatives is higher in wild plants than in " R. recticaulis Borissova in Komarov samples obtained from field crops. Unfortunately, due to the in- " R. heterodonta (Hook.f. & Thomson) Borissova in Komarov tensive collection of R. rosea, the plant is now listed as an endan- " R. sinuata (Royle ex Edgew.) S.H. Fu gered species in many countries. " R. fastigiata (Hook.f. & Thomson) S.H. Fu R. rosea is the most widely researched species of the genus, with " R. imbricata Edgew studies demonstrating antioxidant, adaptogenic, antistress, anti- Europe " R. quadrifida (Pall.) Fisch. & C.A. Mey. " microbial, immunomodulatory, and angiomodulatory properties R. rosea L. " of the extracts [3]. However, other Rhodiola species [4,5] North R. integrifolia Raf. America " R. rhodantha (A. Gray) H. Jacobsen (l" Table 1) have also been studied, including Rhodiola imbricata " R. rosea L. Edgew, Rhodiola crenulata (Hook.f. & Thomson) H. Ohba, and Rhodiola kirilowii (Praeger) H. Jacobsen. The latter species is a tra- ditional Chinese herbal drug for the treatment of altitude sick- ness, and is commonly used by mountaineers, aviators, and as- However, the molecular mechanisms involved in these different tronauts. Rhodiola quadrifida Fisch. & C.A.Mey. is used in tradi- effects remain unclear, making more studies necessary, both tional Mongolian medicine, but has been poorly investigated in vitro and especially in vivo. from a phytochemical and pharmacological perspective [6]. Panossian et al. [9] recently published a study on the modulation In 2010, Panossian et al. [7] published a systematic review of clin- of gene expression in glial cells by treatment with R. rosea extract ical trials to evaluate the level of scientific evidence for the effi- and three isolated compounds. They used the T98G human neu- cacy of R. rosea in the treatment of specific conditions (fatigue, roglial cell line to obtain total RNA, which was transcribed to depression). More recently, a book was published with the entire cDNA, and then submitted to a gene expression profiling proce- body of knowledge and all the ongoing research on R. rosea to dure comprising 561 genes for extract-treated cells, and 640, 601, date, with a substantial number of references from 2010 to and 562 genes for salidroside-, traindrin-, and tyrosol-treated 2013, as well as a few from 2014 [8]. cells, respectively. The authors concluded that Rhodiola extract In addition, the modulatory effects of Rhodiola spp. and other mainly affects genes associated with cellular development and natural antioxidants on angiogenesis have also been recently re- cell-cell signaling, while tyrosol affects genes associated with viewed [6]. Apart from their adaptogenic properties, it seems molecular transport, nervous system development, and cancer. that Rhodiola species also have antitumoral and antiproliferative For its part, triandrin affects genes that play a role in molecular effects, protecting tissues against free radicals and weak and me- transport and inflammation. In a later study, these same authors dium-strength mutagens. One important property of Rhodiola published refined data on the same subject, but only for R. rosea This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. extracts is their ability to inhibit angiogenesis. Even though dif- extracts and principles. ferent Rhodiola species were used, and methods of preparing the In this paper, we discuss the most recent findings on the pharma- extracts differed somewhat in the published studies, the extracts cological effects of Rhodiola species and one of its pure bioactive stimulated specific and nonspecific immunity both in vivo and compounds, salidroside, focusing on their antioxidant, immuno- in vitro. Extracts also inhibited skin neovascularization induced modulatory, antiproliferative, and antitumoral activities.