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Salidroside

Salidroside is a natural , chemically known as 2-(4-hydroxyphenyl)ethyl β-D-glucopyranoside, with the molecular formula C₁₄H₂₀O₇ and a molecular weight of 300.31 g/mol. It is primarily isolated from the roots and rhizomes of various species, such as , R. crenulata, and R. sachalinensis, which thrive in high-altitude regions like the . As a key bioactive constituent in traditional medicines prepared from these adaptogenic plants, salidroside contributes to their reputed ability to enhance stress resistance and overall vitality. This compound has garnered significant attention for its multifaceted pharmacological profile, demonstrating potent antioxidant properties by scavenging (ROS) and mitigating . Salidroside also exhibits neuroprotective effects, protecting against neuronal damage in models of , , and cerebral ischemia. In the cardiovascular system, it offers protection against and , while displaying anti-inflammatory and anti-cancer activities. Additionally, salidroside shows promise in anti-aging, anti-diabetic, and anti-fibrotic applications, with preclinical studies highlighting its role in reducing aging markers and improving insulin sensitivity. As of 2025, recent clinical studies have explored its potential in enhancing exercise performance and , alongside applications in and . Despite its therapeutic potential, salidroside's clinical translation remains limited by challenges such as low , though ongoing research explores synthetic production via engineered microbes and novel delivery systems to enhance its . Its biosynthesis in plants involves the conversion of to followed by , underscoring opportunities for biotechnological optimization.

Introduction

Definition and Chemical Identity

Salidroside is a naturally occurring , chemically known as p-tyrosol β-D-glucopyranoside, and is classified as a phenyl ethanol or phenylethanoid . This compound represents a glycosylated derivative of , where a β-D-glucose moiety is attached to the ethanol backbone, contributing to its and biological in tissues. The molecular formula of salidroside is C₁₄H₂₀O₇, with a of 300.31 g/mol. It is identified by the 10338-51-9 and the PubChem Compound (CID) 159278. These identifiers confirm its unique chemical identity as a bioactive derived from metabolism. As a key active constituent in species of the genus, such as and Rhodiola crenulata, salidroside plays a central role in the adaptogenic properties of these plants, which have been utilized in for enhancing stress resistance and vitality. Its presence in the rhizomes and roots underscores its importance as a primary compound contributing to the pharmacological profile of extracts.

Historical Background

Salidroside, originally known as rhodioloside, has roots in the traditional medicinal uses of species, particularly , which have been employed for centuries across various cultures to combat fatigue, stress, and related ailments. In , , referred to as "Hong Jing Tian," has been utilized since ancient times as an to enhance resistance to physical and mental stress, alleviate asthenia, and promote , often incorporated into formulations for improving and recovery from exhaustion. Similarly, in Russian folk medicine, the plant was valued as a to reduce fatigue, boost physical and mental performance, and support overall resilience, with records dating back to the for treating anxiety, , and stress-induced weakness. In Scandinavian traditions, has been used to enhance physical and mental performance and improve tolerance to environmental stressors. The scientific recognition of salidroside began in the mid-20th century amid Soviet efforts to identify adaptogenic compounds from native plants. In 1967, Soviet researchers A.T. Troshchenko and G.A. Kutikova first isolated salidroside from the roots of Rhodiola rosea and Rhodiola quadrifida, identifying it alongside its aglycone tyrosol and naming it rhodioloside based on its phenolic glycoside structure. This isolation occurred as part of broader adaptogen research in the USSR during the 1960s, where Rhodiola extracts were investigated for their potential to enhance nonspecific resistance to stressors, building on traditional uses and aligning with national interests in performance enhancement for athletes, cosmonauts, and laborers. Early pharmacological investigations in the 1970s and 1980s further highlighted salidroside's role within extracts, particularly in demonstrating anti- effects through animal models. Studies during this period, including those by Saratikov and colleagues, showed that preparations containing salidroside prolonged physical endurance and reduced exhaustion in rats subjected to and other tests, attributing these outcomes to the compound's adaptogenic properties that modulated responses without significant . These findings solidified salidroside's prominence as a key bioactive constituent, bridging with emerging biomedical insights into mitigation.

Chemical Properties

Molecular Structure

Salidroside, chemically designated as 2-(4-hydroxyphenyl)ethyl-β-D-glucopyranoside, features a aglycone—a phenethyl alcohol derivative with a ring—covalently bound to a glucose unit through a β-glycosidic linkage at the anomeric carbon of the sugar. This structure positions the glucose as a β-D-glucopyranoside, where the aglycone attaches via an oxygen bridge from the C1 position of the glucose to the terminal carbon of the 's ethyl chain. The molecule's key functional groups encompass the hydroxyl (-OH) on the para-substituted ring of , which imparts potential; the linkage inherent in the β-glycosidic , connecting the aglycone and moieties; and the ring of the , bearing additional hydroxyl groups at C2, C3, C4, and C6, along with a hydroxymethyl at C5. These elements define salidroside's polarity and reactivity, distinguishing it from aglycone forms like free . Stereochemically, salidroside exhibits the β-anomeric configuration at the glucose C1, ensuring the glycosidic oxygen occupies an equatorial position in the conformation of the ring, which contributes to its stability and biological recognition. In contrast to related compounds like , which employs a phenylpropanoid aglycone with attachment along a propenyl chain, salidroside's phenylethanoid scaffold results in a simpler, more linear architecture.

Physical and Spectroscopic Properties

Salidroside is typically isolated and observed as a white to off-white crystalline , facilitating its handling and storage in settings. This compound demonstrates high in polar solvents, achieving up to 60 mg/mL in at neutral , as well as ready solubility in and ; in contrast, it exhibits low in non-polar solvents such as and acetone. Its thermal properties include a of 159–160 °C, with the compound remaining stable under neutral conditions (around pH 7), though it may hydrolyze under acidic environments. Spectroscopic characterization aids in the identification and purity assessment of salidroside. In ultraviolet-visible (UV-Vis) spectroscopy, it exhibits a characteristic absorption maximum at 220 nm, primarily due to the phenolic hydroxyl group in its structure. (NMR) analysis, particularly ^1H NMR in deuterated solvents like DMSO-d_6 or CD_3OD, shows aromatic protons as doublets around δ 6.68–7.02 (J ≈ 8.4 Hz), reflecting the para-substituted ring, with the anomeric proton of the β-glucosidic linkage appearing near δ 5.0 . () spectroscopy reveals key vibrations, including a broad O–H stretching band at approximately 3400 cm⁻¹ from the phenolic and alcoholic hydroxyls, and C–O stretching at around 1100 cm⁻¹ associated with the glycosidic ether linkage. These spectral features, derived from the backbone, enable reliable analytical confirmation in pharmaceutical and research.

Natural Occurrence and Production

Plant Sources

Salidroside is primarily found in the roots and rhizomes of plants belonging to the genus in the family, with key species including (also known as golden root), Rhodiola crenulata, and Rhodiola sachalinensis. These arctic-alpine perennials are adapted to harsh, cold climates and serve as the main natural sources for the compound. The geographical distribution of these Rhodiola species spans high-altitude regions, including the Arctic tundra, the Himalayan and mountain ranges in , and alpine areas in , with significant diversity in , , and where over 70 species are documented. Cultivation has extended their availability to and parts of to meet demand. In Rhodiola rosea roots, salidroside concentrations typically range from 0.5% to 2% of dry weight, though values can reach up to 1.8% under optimal conditions; levels vary by species, altitude, soil nutrients, and harvest timing, with higher elevations often yielding greater amounts due to environmental stress.

Extraction and Synthesis Methods

Salidroside is primarily obtained through natural extraction from sources such as species, where solvent-based methods like or are commonly employed to isolate the compound from rhizomes and . These traditional solvent extractions involve soaking the plant material in for several hours, followed by and concentration, yielding crude extracts containing salidroside at concentrations typically around 0.5-1% of dry weight. To enhance efficiency, (MAE) has been developed, utilizing microwave energy at 90°C for 20 minutes to rupture plant cells and accelerate , resulting in higher yields and shorter times compared to conventional methods. Additionally, supercritical CO2 extraction with an modifier operates under (200-300 ) and moderate temperatures (40-60°C), offering a green alternative that minimizes residues and achieves salidroside yields up to 1.5% while preserving bioactivity. Chemical synthesis of salidroside typically involves the of , the aglycone precursor, with a glucose moiety using activated donors such as acetobromoglucose in the presence of catalysts like or Lewis acids. The process proceeds via the Koenigs-Knorr reaction, where reacts with protected glucose (e.g., 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide) to form the β-glycosidic bond, followed by deacetylation under basic conditions like in to yield the free salidroside. Overall yields for this multi-step synthesis range from 40-60%, depending on reaction optimization and purification steps, making it suitable for laboratory-scale but less economical for large volumes due to the need for protected intermediates. Biotechnological production leverages microbial fermentation in hosts like or engineered to express glycosyltransferases such as UGT85A1 from , enabling de novo synthesis from glucose or precursors. In , pathways incorporating pyruvate decarboxylase (e.g., ARO10) and produce intermediates, which are then , achieving titers of 56.9 mg/L in optimized shake-flask cultures after of fermentation at 30°C. More recent engineering efforts have achieved titers up to 16.8 g/L in bioreactors as of 2024. Yeast-based systems similarly utilize enhancements and UDP-glucosyltransferases, yielding comparable titers while benefiting from eukaryotic glycosylation machinery for higher fidelity, though scaling to bioreactors remains a focus for industrial viability. Purification of salidroside from crude extracts or fermentation broths often employs high-speed counter-current chromatography (HSCCC), which uses a biphasic system (e.g., ethyl acetate-ethanol-water) to separate based on coefficients, achieving purities exceeding 98% without stationary phases. Alternatively, column chromatography with gradient elution (e.g., chloroform-methanol mixtures) provides effective separation of salidroside from impurities like and rosavins, routinely attaining >98% purity after recrystallization, though it requires more and time than HSCCC. These methods ensure high-purity salidroside suitable for pharmaceutical applications, with overall recovery rates of 70-90% from initial extracts.

Biosynthesis

Biosynthetic Pathway

Salidroside biosynthesis in of the genus primarily occurs through a tyrosine-derived pathway originating from the , which converts phosphoenolpyruvate and erythrose-4-phosphate into aromatic amino acids, including L-tyrosine. In , the committed step involves the direct conversion of L-tyrosine to 4-hydroxyphenylacetaldehyde (4-HPAA) by the bifunctional 4-HPAA (Rr4HPAAS), a neofunctionalized pyridoxal 5'-phosphate-dependent that performs both and without requiring separate activity. This step corrects earlier models proposing sequential and oxidation. Subsequently, 4-HPAA is reduced to tyrosol, the aglycone of salidroside, by NADPH-dependent 4-HPAA reductases such as Rr4HPAR1 and Rr4HPAR2, with Rr4HPAR1 exhibiting higher catalytic efficiency (6.9 μmol min⁻¹ mg⁻¹ protein). The final glycosylation step couples tyrosol with UDP-glucose to yield salidroside, catalyzed by a regio-specific UDP-glucosyltransferase (UGT), including RrUGT33 (also termed RrT8GT) in R. rosea with a catalytic efficiency of 420.6 s⁻¹ mM⁻¹, or RcUGT72B14 in Rhodiola crenulata. These UGTs preferentially modify the 8-position of tyrosol, ensuring specificity in phenylethanoid glycoside formation. An alternative biosynthetic route, proposed in earlier studies and observed in some species, initiates with decarboxylation of to by tyrosine decarboxylase (TYDC), followed by β-hydroxylation or oxidation of to 4-HPAA via tyramine oxidase, and subsequent reduction to . In certain plants, a parallel pathway derives from through by (PAL) to , 4-hydroxylation to , and further reduction steps, though this route shows limited contribution to salidroside in . The pathway enzymes exhibit tissue-specific regulation, with prominent expression in roots where salidroside accumulates, supporting the plant's to environmental pressures in high-altitude habitats.

Metabolic Engineering

Metabolic engineering of salidroside production has focused on reconstructing the biosynthetic pathway in hosts to overcome limitations in natural extraction from plants. Key efforts involve expressing decarboxylase (TYDC) and UDP-glucosyltransferase (UGT) enzymes from , such as RrTYDC and RrUGT72B14 or RrT8GT, to convert to and then to salidroside. In , co-expression of these enzymes with feedback-insensitive variants of ARO4 and ARO7 has enabled production from glucose, achieving titers up to 732 mg/L in fed-batch . Similarly, transient expression in via Agrobacterium-mediated delivery of RrTYDC and RrT8GT has yielded salidroside at up to 2% dry weight in infiltrated leaves. Further advancements in have demonstrated higher efficiencies through chromosomal integration and multi-copy expression of the pathway genes, including plant-derived 4-hydroxyphenylacetaldehyde synthase (4HPAAS) and UGT85A1, resulting in salidroside production of 2.42 g/L from glucose in shake flasks and up to 9.34 g/L in scaled fermenters. Optimization strategies include co-expression of cofactor recyclers, such as sucrose synthase (GmSUS) to regenerate UDP-glucose, the essential glycosyl donor for UGT activity, which has boosted efficiency and titers to 3.8 g/L in coculture systems with S. cerevisiae. Pathway balancing via CRISPR/Cas9-mediated has been applied in microbial hosts to fine-tune and minimize flux to byproducts, though specific implementations for salidroside remain emerging. Recent developments as of 2025 highlight plant-based platforms, with tobacco (Nicotiana tabacum) cell cultures engineered using multi-gene cassettes expressing RrTYDC, Rr4HPAAS, and RrUGT to produce salidroside at approximately 378 μg/g fresh weight from endogenous tyrosine. These yields represent significant improvements over early heterologous efforts, approaching industrial viability. Despite progress, challenges persist, including limited availability of the glycosyl donor UDP-glucose, which competes with cellular metabolism and requires supplementation or recycling modules. Additionally, toxicity from pathway intermediates like tyrosol inhibits host growth, necessitating adaptive evolution or compartmentalization strategies to maintain productivity.

Pharmacological Activities

Antioxidant and Anti-inflammatory Effects

Salidroside demonstrates potent activity through direct scavenging of (ROS), attributed to its phenolic hydroxyl group, which facilitates electron donation and neutralization of free radicals. Additionally, it activates the Nrf2 signaling pathway, promoting nuclear translocation of Nrf2 and subsequent upregulation of downstream enzymes, including (SOD) and (CAT). In cellular assays, salidroside exhibits efficacy in reducing . The compound's anti-inflammatory effects involve inhibition of activation, which suppresses the transcription of pro-inflammatory genes and reduces the production of cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in (LPS)-stimulated macrophages. Salidroside also modulates (MAPK) and c-Jun N-terminal kinase (JNK) signaling pathways, further attenuating inflammatory responses in activated immune cells. In vitro studies have shown that salidroside protects hepatocytes from (H2O2)-induced oxidative damage by decreasing ROS accumulation and preserving cell viability. In vivo assessments in brain tissue demonstrate its ability to reduce , as evidenced by lowered (MDA) levels following exposure to oxidative stressors. In rodent models, salidroside administered at doses of 20-100 mg/kg effectively diminishes MDA levels, indicating reduced and enhanced systemic capacity. These mechanisms contribute to its broader adaptogenic properties under stress conditions.

Neuroprotective and Adaptogenic Effects

Recent studies on salidroside and its derivatives demonstrate inhibition of amyloid-β aggregation and (MAO-B) activity, targeting these pathways to mitigate neurodegenerative processes. In models of cerebral ischemia, salidroside protects neuronal cells through upregulation of (BDNF) expression, reducing and promoting neural repair in the ischemic periphery, while also regulating glutamate metabolism in . These effects contribute to decreased neuronal and improved histological outcomes in ischemic injury. As an adaptogen, salidroside enhances hypothalamic-pituitary-adrenal (HPA) axis balance and reduces cortisol levels in stress-induced models, thereby improving stress resilience without altering baseline hormone function. It also exerts anti-fatigue effects by activating AMP-activated protein kinase (AMPK) and promoting mitochondrial biogenesis, which supports energy metabolism and endurance in exhaustive exercise paradigms. Salidroside readily crosses the blood-brain barrier, enabling direct modulation of neuronal survival pathways such as PI3K/Akt signaling, which inhibits and fosters in various injury models. In antidepressant assays, doses of 10-50 mg/kg reduce immobility time in the forced swim test, indicating enhanced behavioral resilience to stress. In specific disease models, salidroside ameliorates Parkinson's-like symptoms by preserving levels and protecting neurons from mitochondrial dysfunction in MPTP-induced paradigms. It also demonstrates anti-anxiety effects in the elevated plus-maze test, increasing time spent in open arms following acute administration, which supports its role in modulating emotional behaviors.

Research and Applications

Preclinical Studies

Preclinical investigations have explored salidroside's therapeutic potential in multiple disease models, primarily through and experiments using and cell lines. These studies highlight its ability to modulate pathological processes without delving into human applications. In anti-cancer research, salidroside has shown inhibitory effects on tumor growth in xenograft models. For instance, in non-small cell xenografts in nude mice, intraperitoneal administration of salidroside at 50 mg/kg every other day significantly reduced tumor volume by promoting and modulating the , including upregulation of T cells and dendritic cells while suppressing regulatory T cells. Similar antitumor activity was observed in xenografts, where salidroside treatment inhibited and , leading to smaller tumor sizes compared to controls. Cardioprotective effects of salidroside have been evidenced in models of . In rats subjected to ischemia-reperfusion injury, salidroside pretreatment reduced infarct size and preserved cardiac function by upregulating anti-apoptotic expression and inhibiting caspase-3 activation. Administration in acute rat models also attenuated and improved systolic performance, with outcomes linked to pathways such as Akt . For anti-diabetic activity, salidroside improved insulin sensitivity in (STZ)-induced diabetic models. In high-fat diet/STZ-treated mice, oral salidroside lowered fasting blood glucose levels by approximately 25-30% and reduced serum insulin, alleviating and through enhanced insulin signaling. These effects were consistent across models, where salidroside mitigated renal damage while restoring glucose . Additional preclinical findings include hepatoprotective benefits against acetaminophen (APAP) toxicity. In APAP-challenged mice, salidroside pretreatment decreased liver enzyme elevations (/) and histopathological damage by preserving levels and inhibiting , resulting in survival rates over 80% compared to untreated controls. In models, such as collagen-induced arthritis in rats and mice, salidroside reduced joint inflammation and paw swelling in 2025 studies, supporting its anti-arthritic potential through immune modulation. Regarding pharmacokinetics, preclinical data indicate salidroside's oral bioavailability is approximately 32% in rats, with rapid absorption leading to peak plasma concentrations within 25-30 minutes. The plasma half-life ranges from approximately 0.7 to 2 hours, influenced by formulation and species, as observed in rodent models following oral dosing. These properties, including brief references to Nrf2 pathway involvement in oxidative stress reduction, underscore salidroside's suitability for further translational research.

Clinical Trials and Therapeutic Potential

Clinical trials on salidroside in humans remain limited, with the majority of evidence derived from studies on extracts where salidroside serves as a primary bioactive component. Recent investigations have begun to isolate the effects of pure or biosynthetic salidroside, particularly in contexts of physical performance and adaptation. A key example is an exploratory randomized, double-blind, placebo-controlled trial conducted in 2024 involving 50 healthy active young adults (aged 21 ± 4 years), who received 60 mg/day of biosynthetic salidroside (30 mg twice daily) or for 16 days. Participants underwent high-intensity intermittent exercise testing, revealing that salidroside significantly enhanced predicted oxygen uptake (p < 0.01), reduced exercise-induced increases in as a marker of muscle damage (p = 0.02), and mitigated declines in mood and rises in observed in the group (p < 0.01 for fatigue-inertia and friendliness scores). Time-to-exhaustion also improved in the salidroside group compared to (p = 0.03). As of 2025, additional studies on fermented salidroside have confirmed efficacy in , enhancing performance and in active individuals. These findings indicate salidroside's potential as an for reducing fatigue and supporting in athletic populations, with stable mood maintenance during intense physical demands. No serious adverse events were reported, supporting the compound's tolerability at low doses. Broader human data on psychiatric applications, such as anxiety and stress reduction, are referenced in reviews but primarily stem from Rhodiola-based interventions rather than isolated salidroside. Therapeutic potential extends to adjunctive roles in stress-related conditions, informed by the exercise trial's mood-stabilizing effects and preclinical evidence of adaptogenic properties. Emerging preclinical research highlights possibilities in through pathways, including modulation of Th17/Treg balance and suppression, though human validation is pending. Similarly, in vitro and animal studies suggest neuroprotective benefits, such as MAO-B inhibition for adjunct therapy, but no dedicated human trials have confirmed these yet. Dosing in available human studies is 60 mg/day over 7-16 days, deemed safe with variable efficacy across outcomes, underscoring the need for larger randomized controlled trials to establish broader clinical utility.

Safety and Toxicology

Toxicity Studies

Acute toxicity studies of salidroside in Sprague-Dawley rats have demonstrated a high safety margin, with an oral LD50 exceeding 5000 mg/kg body weight and no observed mortality, clinical signs, or gross pathological changes following single doses up to this level. No organ damage, including to the liver or kidneys, was reported in these assessments, indicating minimal risk from acute exposure. Subchronic toxicity evaluations, including a 28-day repeated oral dose study in male and female Sprague-Dawley rats at doses up to 2000 mg/kg/day, showed no adverse effects on body weight, food consumption, , , or organ histopathology. Genotoxicity assessments, such as the using typhimurium strains, were negative for mutagenicity at concentrations up to 5000 µg/plate, confirming no DNA-damaging potential. Similarly, no was evident, with normal liver enzyme levels (e.g., , ) and absence of histopathological alterations in the liver. Although a dedicated 90-day study specific to salidroside is limited, related extract studies containing salidroside at equivalent doses support these findings of safety. Reproductive toxicity investigations in pregnant Sprague-Dawley rats administered salidroside at doses ranging from 125 to 500 mg/kg showed no maternal , embryonic , or teratogenic effects, with normal fetal and no structural abnormalities observed. Recent studies from on bioengineered, nature-identical salidroside in rats confirmed its safety profile, revealing no adverse impacts on blood chemistry parameters (e.g., glucose, ) or histopathological features in major organs after repeated dosing up to 2000 mg/kg/day. Overall, preclinical data align with limited human data suggesting good tolerability, such as a 2024 randomized, double-blind, placebo-controlled trial in healthy adults where 60 mg/day for 16 days resulted in no adverse events and normal blood parameters.

Contraindications and Interactions

Due to limited specific data on isolated salidroside, precautions from studies on (which contains salidroside as a major component) suggest avoiding use during and to minimize potential risks to the or infant. Based on Rhodiola data, individuals with should avoid salidroside, as it may exacerbate manic episodes through adaptogenic and stimulant-like effects observed in the plant extract. For those with autoimmune conditions, such as or , caution and medical monitoring are advised when using salidroside, as may stimulate immune activity and potentially counteract immunosuppressant therapies; salidroside-specific effects remain understudied. Salidroside may interact with (MAO) inhibitors, potentially potentiating their effects and increasing the risk of tyramine-like hypertensive crises, although studies show minimal direct MAO-A or MAO-B inhibition by salidroside itself at clinically relevant concentrations. It can enhance the sedative effects of central nervous system depressants, such as benzodiazepines or barbiturates, leading to increased drowsiness and impaired coordination, based on observations with . In vitro evaluations indicate that salidroside does not significantly inhibit or induce , suggesting low risk of altering the metabolism of statins like or simvastatin when co-administered. Patients with hepatic impairment should use salidroside with dose adjustments and , given its partial , despite observed hepatoprotective effects in preclinical models. When combining salidroside with antidepressants, such as SSRIs or MAOIs, close is recommended based on data to prevent enhanced side effects, including potential , as noted in case reports and interaction warnings for the up to 2025; salidroside-specific risks require further study.