paeoniflorin

Paeoniflorin

1. Identity, Botanical Source, and Chemical Nature

Paeoniflorin (PF; molecular formula C₂₃H₂₈O₁₁) is a water-soluble monoterpene bicyclic glycoside extracted from Paeonia lactiflora Pall. (family Paeoniaceae). It was first isolated from the roots of Paeonia albiflora and named by Shibata et al. (1963), who identified it as a D-glucoside with a benzoylated C10-compound. Further studies confirmed that paeoniflorin is a monoterpene glucoside whose basic skeleton is a pinane derivative.

Paeoniflorin has a molecular weight of 480 g/mol and is a β-glucoside of paeoniflorigenin. Its key structural components include a glucose moiety (C₆H₁₂O₆), a benzoyl moiety (COC₆H₅), and a cage-like pinane skeleton.

First isolated in 1963, its full chemical structure was determined in 1972. Paeoniflorin has been considered the characteristic chemical constituent of Paeoniaceae plants since its first report and is increasingly used in the clinical treatment of many diseases because it has a variety of pharmacological activities.

Paeonia lactiflora, a perennial herb of the Paeoniaceae family, is widely distributed in China, Japan, South Korea, Mongolia, and Russia (Far East Siberia). The secondary metabolites in Paeoniaceae are complex, with more than 300 chemical components identified, mainly including monoterpene glycosides, triterpenoids, flavonoids, tannins, phenolic acids, sugars, steroids, and volatile constituents. Paeoniflorin is distributed throughout the plant, including flowers, stems, leaves, fruits, seeds, and rhizomes.

Related Compounds and the Total Glucosides of Peony (TGP) Preparation

A water/ethanol extract of the root is known as total glucosides of peony (TGP), which contains more than 15 components. Paeoniflorin is the most abundant ingredient and accounts for the pharmacological effects observed with TGP in both in vitro and in vivo studies. TGP predominantly comprises five monoterpene glycosides including paeoniflorin, oxypaeoniflorin, paeonin, albinorin, and benzoylpaeoniflorin. Paeoniflorin is the most abundant, accounting for approximately 90% of the active components and the pharmacological effects of TGP. TGP has been approved as a disease-modifying drug for RA since 1998 by the China Food and Drug Administration and is now widely used to treat RA in China.

TGP is a Chinese patent medicine made of total glucosides extracted from white peony. The dosage form of TGP on the market is a capsule, standardized at 0.3 g, with each capsule containing no less than 104 mg paeoniflorin.

Paeoniflorin is mainly extracted from the roots of Paeoniaceae plants, but this has disadvantages including low yield, difficulty in separation, and wastage of plant resources. Although paeoniflorin has been synthesized by chemical methods, it is not used in actual production because of its complicated process, high production cost, and contaminated production process.

2. Traditional and Historical Use

The dried root without bark of P. lactiflora Pall., namely Radix Paeoniae Alba, has been used as a medicinal herb in traditional Chinese medicine for centuries, where it is called Bái Sháo (literally: "White Peony"). It was first recorded in Shen Nong's Herbal Classic (Shennong Bencao Jing) and has been used for nearly 1,000 years.

In China, Korea, and Japan, a decoction of the dried root without bark of Paeonia lactiflora Pall. has been used in the treatment of rheumatoid arthritis, systemic lupus erythematosus, hepatitis, dysmenorrhea, muscle cramping and spasms, and fever for more than 1,200 years.

The dried root without bark of P. lactiflora, known as Radix Paeoniae Alba, is dug in summer or autumn from cultivated plants that are 4–5 years old and cleaned with water. After removal of the bark and rootlets, it is boiled in water for a short while, dried in the sun, and then sliced.

A decoction of Radix Paeoniae has been used in the treatment of headaches, dizziness, costal and abdominal pain, spasmodic pain of the limbs, anemia, menstrual disorders, spontaneous sweating, and night sweating in traditional Chinese medicine.

Paeonia lactiflora Pall. (also known as shaoyao) is divided into Radix Paeoniae Rubra (RPR, also known as chishao or red peony root) and Radix Paeoniae Alba (RPA, also known as baishao or white peony root). Both forms appear throughout the classical pharmacopoeia of Chinese medicine, with white peony root being more commonly used for nourishing and blood-regulating purposes and red peony root being used to invigorate blood circulation.

Classic traditional Chinese medicine formulas containing paeoniflorin, such as Xiaoyao San, Chaihu Shugan San, and Sini San, have been used and proven to significantly improve depressive symptoms.

A plurality of traditional Chinese medicinal preparations containing Paeonia lactiflora include anti-cerebral-thrombosis tablets, brain-benefiting and rehabilitation capsules, paralysis-treating tablets, resurrecting pills, and collateral-activating pills, mainly used for treating cardiovascular and cerebrovascular diseases, neuralgia, hypertension, abortion, and dysmenorrhea.

3. Key Constituents and Established Mechanisms of Action

Paeoniflorin, a water-soluble monoterpene glycoside isolated from Paeonia lactiflora Pall., has a wide range of medicinal properties including anti-inflammatory, antioxidant, antithrombotic, anticonvulsive, analgesic, cardioprotective, neuroprotective, hepatoprotective, antidepressant-like, antitumoral, and immune-regulatory activities, as well as enhancing cognition and attenuating learning impairment.

Anti-inflammatory and Immunomodulatory Mechanisms

Paeoniflorin's molecular actions include the downregulation of pro-inflammatory cytokines, modulation of immune cell subsets, and interference with key signalling pathways such as MAPK and NF-κB, which are pivotal in the pathogenesis of autoimmune disorders.

In rats, paeoniflorin treatment (5 mg/kg i.p., twice per day) for 14 days inhibited activation of astrocytes and microglia following transient middle cerebral artery occlusion and reperfusion. In this study, paeoniflorin was found to downregulate pro-inflammatory mediators (TNF-α, IL-1β, iNOS, COX-2, and 5-LOX) in plasma and brain by blocking JNK and p38 MAPK activation and NF-κB signaling but enhancing ERK activation.

Paeoniflorin significantly inhibited the generation of reactive oxygen species (ROS), upregulated the expression of SIRT1 mRNA, and downregulated the expression of nuclear NF-κB, p65, NLRP3, Caspase-1, and GSDMD-N in vitro.

Neuroprotective Mechanisms

Neuroprotective mechanisms of paeoniflorin are closely correlated to activating adenosine A1 receptor, ameliorating the function of cholinergic nerves, regulating ion channel homeostasis, retarding oxidative stress and apoptosis of neurocytes, promoting nerve growth, having an influence on astrocytes, and being able to penetrate through the blood-brain barrier.

A review of the pharmacological aspects of paeoniflorin summarized possible mechanisms including restoration of mitochondrial function; inhibition of neuroinflammation, oxidative stress, and cellular apoptosis; activation of adenosine A1 receptor, cAMP response element-binding protein (CREB) and extracellular signal-regulated kinase 1/2 (ERK1/2); and enhancement of brain-derived neurotrophic factor and serotonin function, in the prevention of disorders such as cerebral ischemia, subarachnoid hemorrhage, vascular dementia, Alzheimer's disease, Parkinson's disease, depression, post-traumatic stress disorder, and epilepsy.

Another possible mechanism for the neuroprotective effect of paeoniflorin is its conversion to benzoic acid, an intermediate compound that can be transported to the brain via monocarboxylate transporter 1 (MCT1) and produce neuroprotective effects in schizophrenia, dementia, and early-phase Alzheimer's disease.

Analgesic Mechanisms

Mechanisms including adenosine A1 receptor activation and inhibition of neutrophil infiltration, NF-κB transcription, NLRP3 inflammasome activation, microglial MMP-9/2 activity, ASK1 inhibition, and p38 inhibition may mediate the analgesic effect of paeoniflorin.

4. Scientific Evidence by Area of Use

4.1 Rheumatoid Arthritis and Autoimmune Joint Disease

This is the area where paeoniflorin (via TGP) has the most substantial clinical evidence base.

Randomized controlled trials (RCTs) on the efficacy and safety of TGP combined with methotrexate (MTX) and leflunomide (LEF) for RA were examined. Eight RCTs were included in the final meta-analysis. Pooled results showed better therapeutic effects against RA in the TGP-treated group (RR = 1.10, 95% CI: 1.04–1.16).

Compared with methotrexate alone, the use of TGP combined with MTX exhibited better therapeutic effects for the treatment of RA. In addition, TGP combined with MTX caused a more significant decrease in erythrocyte sedimentation rate (ESR) and swollen joint count (SJC). A total of eight RCTs involving 522 participants were included in this meta-analysis. Due to the poor methodological quality of included trials, well-designed, multi-center, and large-scale RCTs are necessary to draw a more definitive conclusion.

A multicentre RCT including 370 patients with RA found that TGP might be effective in improving joint function without severe adverse effects.

Total glucosides of paeony (TGP) have been confirmed to reduce hepatotoxicity caused by methotrexate and leflunomide in rheumatoid arthritis. Nevertheless, high-quality evidence-based meta-analysis data on the issue remain unavailable.

A meta-analysis indicated that TGP adjuvant therapy might alleviate the incidence of hepatic adverse effects and leukopenia for RA treatment compared to non-TGP therapy. The clinical safety of TGP adjuvant therapy warrants further investigation in experimental studies.

Evidence strength: Moderate. Multiple meta-analyses of RCTs exist for TGP in RA, but the methodological quality of the individual trials has consistently been noted as poor or insufficient. Most evidence comes from Chinese-language trials, which introduces potential publication and language bias. TGP is regulatory-approved in China as a disease-modifying antirheumatic drug (DMARD), but does not yet hold regulatory approval in Western markets.

4.2 Neuroprotection and Neurological Disorders

According to current study findings, paeoniflorin can ameliorate the decline of memory and learning capacities in many dementia model animals, and has demonstrated effects in protecting against cerebral ischemia injury, treating Parkinson's disease, relieving pain, and improving neural synapse plasticity.

Cerebral Ischemia: In a rat model of cerebral infarction (middle cerebral artery occlusion for 15 min followed by reperfusion), paeoniflorin administered at 20 mg/kg intraperitoneally for 6 days reduced the neurological deficit score, improved motor function, suppressed neuronal apoptosis, and promoted neurogenesis. The underlying mechanisms involved inhibition of neurological apoptosis and inflammation by nicotinic acetylcholine receptors.

Alzheimer's Disease: Pre-clinical studies support the utility of paeoniflorin for the treatment of neurodegenerative diseases such as Alzheimer's disease. Evidence in this area is limited to in vitro and transgenic mouse models; no human clinical trials have been published.

Parkinson's Disease: In vitro, paeoniflorin had neuroprotective effects against MPTP⁺-induced damage and apoptosis through the Bcl-2/Bax/caspase-3 pathway in PC12 cells. In the 6-hydroxydopamine (6-OHDA) rat model of Parkinson's disease, paeoniflorin improved behavioral symptoms, delayed dopaminergic neuron loss, and attenuated loss of dopamine and its metabolites in the substantia nigra. Paeoniflorin modulated ASIC1a expression, decreased α-synuclein (α-SYN), and lessened autophagic dysfunction.

Paeoniflorin administration may ameliorate MPTP-induced impairment of spontaneous motor performance and inhibit MPTP-induced loss of dopaminergic neurons by increasing the expression of dopaminergic transporters and tyrosine hydroxylases, decreasing MAO-B and caspase-3/9 activity, or increasing Akt activity via a mechanism related to adenosine A1 receptor activation.

Evidence strength (neurological): Preliminary. The overwhelming body of evidence is from animal and in vitro studies. No registered human clinical trials of paeoniflorin monotherapy for Alzheimer's disease, Parkinson's disease, or cerebral ischemia have been reported in the literature reviewed. Clinical translation remains an open research question.

4.3 Depression and Mood Disorders

Numerous preclinical studies have shown that paeoniflorin has preventive and therapeutic effects on various neurological diseases, particularly in the prevention and treatment of depression.

It has been proposed that paeoniflorin may exert an antidepressant effect by regulating cell inflammation, synaptic function, NF-κB signaling pathway, and intestinal inflammation. These results were derived from network pharmacology combined with in vivo and in vitro experimental validation.

Studies showed that paeoniflorin treatment decreased the degree of depression in chronic restraint stress (CRS) mice. Further analysis showed that the expression of ERK1/2 proteins was significantly downregulated in CRS mice, while paeoniflorin could elevate the expression of ERK1/2 proteins. Inhibiting the ERK1/2 pathway could aggravate depressive behavior, while the condition could be partially relieved when treated with paeoniflorin.

Paeoniflorin, a monoterpene glycoside analog possessing anti-inflammatory attributes, exhibits therapeutic efficacy on depression-like behavior in mice. Studies evaluating antidepressant effects used the chronic unpredictable mild stress (CUMS) model and investigated the precise neural sequence associated with the inflammatory process.

Pharmacodynamics tests showed that paeoniflorin had significant antidepressant activity in preclinical models, but its oral bioavailability was measured at 2.32%.

Paeoniflorin was converted into benzoic acid by the gut microbiota and was mainly excreted through the urine with the gut metabolite benzoic acid as the prominent excreted form. Paeoniflorin could also regulate the composition of the gut microbiota by increasing the abundance of probiotics.

Evidence strength (depression): Preliminary to weak for human use. All controlled evidence is from animal models (rodent chronic stress models). The classical TCM formulas containing paeoniflorin (e.g., Xiaoyao San) have some clinical evidence, but isolating the contribution of paeoniflorin itself is not possible from such data. No adequately powered, placebo-controlled human RCTs of paeoniflorin monotherapy for depression have been identified.

4.4 Cardiovascular System

Paeoniflorin is an active component found in Paeonia lactiflora which is used to treat smooth muscle spasms and pain and to protect the cardiovascular system.

Reviews have approached the usage of paeoniflorin for neurological disorders, analgesia, antidepressants, neuroprotection, and immunomodulation; a review specific to paeoniflorin's protective effect on the cardiovascular system is notably lacking.

Basic experiments have revealed hepatoprotective effects of paeoniflorin, such as its ability to interfere with bile acid metabolism and pivotal inflammation-related targets, as well as its capacity to ameliorate cholestatic liver injury.

Evidence strength (cardiovascular): Predominantly preclinical. Mechanistic data in animal models are available, but rigorous human clinical evidence for cardiovascular endpoints is absent from the published literature to date.

4.5 Diabetes and Metabolic Disorders

Paeoniflorin improves diabetes and its complications through reducing blood sugar, enhancing insulin sensitivity, regulating gut microbiota and autophagy, restoration of mitochondrial function, regulation of lipid metabolism, anti-inflammation, anti-oxidative stress, inhibition of apoptosis, and immune regulation.

Paeoniflorin, a monoterpenoid glycoside compound, has garnered substantial attention owing to its potential therapeutic efficacy in diabetes management, with pharmacological effects, pharmacokinetics, and toxicity being systematically reviewed.

Evidence strength (metabolic): Preliminary to moderate for mechanistic understanding, but primarily preclinical. Clinical human trial data in diabetes are limited.

4.6 Pain and Analgesia

The analgesic effect of TGP was confirmed in various animal models of pain, which may be mediated partly by the adenosine A1 receptor.

Current findings show that the adenosine A1 receptor plays an important role in paeoniflorin's analgesic effects, while muscarinic cholinergic receptor, opiate receptor, calcium ion channel, and NF-κB may also play a part.

Evidence strength (pain): Preliminary. Evidence is predominantly from animal models. Clinical analgesic effects are inferred from the traditional use of peony root preparations and animal pharmacology but have not been definitively established in adequately powered human trials of paeoniflorin as a monotherapy.

4.7 Hepatoprotective Effects

Paeoniflorin possesses antioxidative, anti-inflammatory, and hepatoprotective effects. Because of its safety and immunoregulatory effects, paeoniflorin has been widely used in treating various inflammatory and autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome, allergic contact dermatitis, and psoriasis.

In classical Chinese herbal textbooks and the Pharmacopoeia of China, Paeonia lactiflora Pallas is often referred to as a protective agent for the liver.

Evidence strength (hepatoprotective): Preliminary. Hepatoprotective effects are well-characterized in animal models. One of the clinically noted benefits of TGP in the RA setting is a reduction in drug-induced hepatotoxicity from methotrexate and leflunomide, which is supported by meta-analytic data, but this represents an adjunctive protective action rather than a primary hepatotherapy.

5. Body Systems and Health Areas

• Musculoskeletal and Immune System: Anti-inflammatory and immunomodulatory activity relevant to rheumatoid arthritis, systemic lupus erythematosus, and other autoimmune conditions.
• Central Nervous System: Neuroprotective activity relevant to cerebral ischemia, Alzheimer's disease, Parkinson's disease, vascular dementia, and epilepsy; antidepressant and anxiolytic effects in preclinical models.
• Cardiovascular System: Preclinical data on cardioprotective effects, smooth muscle relaxation, and endothelial protection.
• Hepatobiliary System: Hepatoprotective and antifibrotic effects demonstrated in animal models; clinical evidence via reduction of drug-induced liver injury in RA patients on conventional DMARDs.
• Endocrine and Metabolic Systems: Preclinical evidence for blood-glucose reduction, insulin sensitization, and lipid metabolism modulation.
• Gastrointestinal System: Preclinical evidence for effects on gut motility, intestinal inflammation, and gut microbiota composition.
• Reproductive/Gynecological System (Traditional): Historically used for dysmenorrhea and menstrual disorders.

6. Pharmacokinetics and Bioavailability

Paeoniflorin possesses the characteristics of rapid absorption, wide distribution, rapid metabolism, and renal excretion.

Poor permeation, P-glycoprotein (P-gp)-mediated efflux, and hydrolysis via a glucosidase all contribute to the poor bioavailability of paeoniflorin.

Pharmacodynamics tests showed that paeoniflorin had significant antidepressant activity in models, but its oral bioavailability was measured at 2.32%.

The absorption site of paeoniflorin is mainly the intestine, and the absorption rate of the aglycone is 48 times that of paeoniflorin.

Paeoniflorin is widely distributed in various tissues after entering the systemic circulation, mainly in the stomach, intestine, and heart. Paeoniflorin has a smaller ability to penetrate the blood-brain barrier (permeability coefficient: 0.587 × 10⁻⁶ to 0.705 × 10⁻⁶ cm/s).

The results on the distribution of paeoniflorin in the brain suggest that paeoniflorin may be able to directly cross the blood-brain barrier. Although paeoniflorin can enter the brain when injected subcutaneously, intravenously, or intraperitoneally, the precise mechanism by which it crosses the blood-brain barrier is not yet known.

The metabolism of paeoniflorin is divided into two pathways: intestinal flora metabolism and enzyme metabolism in vivo.

Orally administered paeoniflorin is metabolized into three metabolites — paeonimetabolin I–III — by intestinal bacteria. Paeonimetabolin-I, a major metabolite, has been demonstrated to be a potent anticonvulsant.

Paeoniflorin is converted into benzoic acid by the gut microbiota, and it is mainly excreted through the urine with benzoic acid as the prominent excreted form.

Plasma concentrations of paeoniflorin and its major metabolite paeonimetabolin I (PM-I) were estimated after oral administration to rats at doses of 0.5 and 5 mg/kg. The maximal plasma concentrations of paeoniflorin were 9.9 and 20.3 ng/mL, and those of PM-I were 16.5 and 101.7 ng/mL at each dose, respectively. The times to Cmax of paeoniflorin were 11.6 and 13.3 min, and those of PM-I were 60 and 80 min, respectively.

7. Dosage Forms and Dosages Reported in Studies

The following dosages are those specifically stated in the cited research sources. These reflect dosages used in experimental and clinical contexts and are not recommendations.

• TGP capsules, the standardized market form, contain 0.3 g per capsule with no less than 104 mg paeoniflorin per capsule. This is the principal clinical form used in the Chinese RA treatment trials.
• In rat stroke models, paeoniflorin was administered at 5 mg/kg i.p., twice per day for 14 days.
• In a rat cerebral ischemia-reperfusion study, paeoniflorin was administered at 20 mg/kg intraperitoneally for 6 days.
• In a multiple sclerosis-like rat model, paeoniflorin was administered orally at 50 mg/kg and 100 mg/kg, both as monotherapy and in combination with vitamin B12 (30 mg/kg p.o.).
• In a pharmacokinetic interaction study, paeoniflorin was orally administered to rats at 20 mg/kg.

No standardized human dosage for isolated paeoniflorin has been established by any international regulatory or pharmacopeial body outside of China. Clinical human evidence is predominantly derived from TGP as a standardized preparation rather than pure paeoniflorin isolate.

8. Safety Considerations and Interactions

General Toxicity Profile

Toxicity studies have suggested that paeoniflorin has low acute toxicity, minimal subacute and chronic toxicity, and no genotoxic or mutagenic toxic effects. Paeoniflorin has a low toxicity at effective concentration.

Paeoniflorin, as a natural glycoside metabolite with a wide margin of safety and good tolerance, exhibits certain toxicity at high concentrations.

Adverse Effects of TGP in Clinical Use

Total glucosides of paeony, as used adjunctively for rheumatoid arthritis patients, has been increasingly used as adjunctive therapy. Though TGP could mitigate the unanticipated adverse effects during conventional treatment of RA, high-quality evidence-based meta-analysis data on this subject are still insufficient.

Drug–Drug Interactions and CYP450 Considerations

Glycyrrhizin (from licorice root) could affect the pharmacokinetics of paeoniflorin, potentially by decreasing its absorption through inducing the activity of P-gp or through increasing its clearance rate in rat liver by inducing the activity of CYP450 enzymes.

Researchers have reported that the high content of licorice in the classical shaoyao-gancao (peony-licorice) decoction could reduce the bioavailability of paeoniflorin and albiflorin.

Peimine, another compound used in Chinese medicine, has been reported to exert inhibitory effects on the activity of various cytochrome P450 enzymes (CYP450s), including CYP3A4, 2E1, and 2D6, which are key mediators during the pharmacokinetics of paeoniflorin. When peimine and paeoniflorin were co-administered, the Cmax and AUC of paeoniflorin were significantly increased.

In a Caco-2 cell model, paeoniflorin was transported 48-fold slower than its aglycone (paeoniflorigenin). Absorptive transport of paeoniflorin was significantly increased by sinomenine (38%), verapamil (27%), and cyclosporine A (41%), whereas its secretory transport was significantly decreased by the same agents.

Methodological Limitations on the Safety Evidence Base

Differences in standardized methods between traditional formulations, such as extraction processes, dosages, and inherent metabolite variability in formulations, may affect the interpretation of results and clinical applications.

Due to the poor methodological quality of included trials, well-designed, multi-center, and large-scale RCTs are necessary to draw more definitive conclusions regarding efficacy and safety.

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