Polygala tenuifolia

Polygala tenuifolia is a root used in traditional Chinese medicine for its ability to improve memory and protect against cognitive ailments. Limited human evidence suggests Polygala tenuifolia cannot improve memory, but may improve spatial awareness and organization.

This page features 79 unique references to scientific papers.

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All Essential Benefits/Effects/Facts & Information

Polygala tenuifolia, also known as Yuan Zhi, is a root used in Traditional Chinese Medicine.

It has traditionally been used for its protective effects on the brain.

Preliminary animal evidence suggests that Polygala tenuifolia has an antidepressant effect in rats. Polygala tenuifolia_ may improve cognition, but more research is needed to confirm this effect.

Rodent research suggests that Polygala tenuifolia is similar in mechanism and effectiveness to ketamine, which interacts with N-methyl-D-aspartic acid and its receptors. Rodent studies assessing Polygala tenuifolia’s anti-amnesiac and Adaptogen-like properties suggest that the herb can increase the level of compounds responsible for brain growth, like nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF).

Though Polygala tenuifolia supplementation may slightly increase cognitive ability in elderly people, it has limited effect on healthy adults. Supplementing Polygala tenuifolia can improve spatial organization and recognition, but it does not improve short- or long-term memory formation, as measured by free or cued recall. Much more research is needed to determine if Polygala tenuifolia qualifies as a Nootropic.

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How to Take

Recommended dosage, active amounts, other details

The only human studies on Polygala tenuifolia have used 100mg of an ethanolic extract called BT-11, three times a day, for a total daily dose of 300mg.

A Traditional Chinese Medicine remedy suggests taking 3-9 g (dry weight) of Polygala tenuifolia root through a water decoction, like tea or soup, to reduce forgetfulness.

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Human Effect Matrix

The Human Effect Matrix looks at human studies (it excludes animal and in vitro studies) to tell you what effects polygala tenuifolia has on your body, and how strong these effects are.

Grade Level of Evidence
Robust research conducted with repeated double-blind clinical trials
Multiple studies where at least two are double-blind and placebo controlled
Single double-blind study or multiple cohort studies
Uncontrolled or observational studies only
Level of Evidence
? The amount of high quality evidence. The more evidence, the more we can trust the results.
Outcome Magnitude of effect
? The direction and size of the supplement's impact on each outcome. Some supplements can have an increasing effect, others have a decreasing effect, and others have no effect.
Consistency of research results
? Scientific research does not always agree. HIGH or VERY HIGH means that most of the scientific research agrees.
Cognitive Decline Minor Moderate See 2 studies
A possible reduction in cognitive decline as assessed by CEMAD scores, although MMSE scores did not experience a significant benefit with supplementation at this moment in time.
Spatial Processing Minor - See study
There appears to be an increase in spatial processing seen with supplementation in otherwise healthy humans due to less errors on spatial organizational tasks.
Working Memory Minor - See study
BT-11 appears to have some efficacy in improving immediate recall in otherwise healthy adults, although it did not have this efficacy in short term recall (cued or free)
Memory - Very High See 2 studies
There have been no detectable increases in long term (20 minute) recall, either with or without cues, associated with supplementation at this point in time.
Verbal Fluency - - See study
No significant improvements in verbal fluency noted in elderly adults with memory complaints supplementing this herb.

Scientific Research

Table of Contents:

  1. 1 Sources and Composition
    1. 1.1 Origin and Composition
    2. 1.2 Sources and Structure
    3. 1.3 Variants and Formulations
  2. 2 Molecular Targets
    1. 2.1 PI3K/Akt
  3. 3 Pharmacology
    1. 3.1 Absorption
    2. 3.2 Distribution
    3. 3.3 Elimination
  4. 4 Neurology
    1. 4.1 Adenosinergic Neurotransmission
    2. 4.2 Adrenergic Neurotransmission
    3. 4.3 Cholinergic Neurotransmission
    4. 4.4 Dopaminergic Neurotransmission
    5. 4.5 Glutaminergic Neurotransmission
    6. 4.6 Serotonergic Neurotransmission
    7. 4.7 Miscellanous Mechanisms
    8. 4.8 Bioenergetics
    9. 4.9 Neurogenesis
    10. 4.10 Neuroprotection
    11. 4.11 Neuroinflammation
    12. 4.12 Sedation
    13. 4.13 Anxiety and Stress
    14. 4.14 Depression
    15. 4.15 Memory and Learning
  5. 5 Inflammation and Immunology
    1. 5.1 Macrophages
    2. 5.2 Virology
  6. 6 Interactions with Hormones
    1. 6.1 Corticosteroids
  7. 7 Interactions with Oxidation
    1. 7.1 Superoxide
  8. 8 Interactions with Organ Systems
    1. 8.1 Liver
  9. 9 Interactions with Cancer Metabolism
    1. 9.1 Lung
    2. 9.2 Ovarian
  10. 10 Sexuality and Pregnancy
    1. 10.1 Seminal Properties
  11. 11 Interactions with Medical Conditions
    1. 11.1 Alzheimer's Disease
    2. 11.2 Parkinson's
  12. 12 Safety and Toxicology
    1. 12.1 General
    2. 12.2 Case Studies

1Sources and Composition

1.1. Origin and Composition

Polygala tenuifolia (of the family Polygalaceae) is a Traditional Chinese Medicine and one of the 50 fundamental herbs under the name of yuan zhi, with the roots of the plant used primarily for the treatment of forgetfulness or amnesia and as a general treatment of cognitive ailments such as dementia. It is the most common plant used for ailments of the central nervous system (CNS) in traditional Chinese medicine (mostly forgetfulness and aging) and second most cited for memory enhancement (behind only Curculigo orchoides aka. xian mao).[1]

The species polygala senega, commonly called Senega Root, may also share the name of Yuan Zhi and polygala tenuifolia is sometimes called Chinese Senega; it is not known if the two roots are interchangeable.

Polygala tenuifolia is a plant whose roots have been traditionally used for the treatment of cognitive ailments.

Polygala tenuifolia roots (the main medicinal component of the plant) contain:

  • Tenuifolisides A, B, and C[2][3] (sucrose esters[4]) which are thought to be neuroprotective.[3]

  • 3,6'-disaponylsucrose (DISS), a major acetylated sucrose molecule in the root[5][3]

  • The tenuifoliose series of molecules (oligosaccharide multiesters) including tenuifoliose A, B, C, F, G, H, I, J, K, L, M, N, O, P, S, T, V, W, and X[4][6]

  • Tenuifolin[7] at around 0.006% the dry weight of the root,[8] a metabolite of tenuigenin[9] found in the 80% ethanolic extract[10]

  • The saponins tenuigenin,[11][12] senegenin and senegenin III,[4][13] polygalasaponin F (PGSF),[14][15] tenuifoside A,[16] and polygalasaponin XXXII[17] which likely underlie some of the cognitive-enhancing properties of the roots

  • The onjisaponin series of molecules including V, E, L, G, F, O, S, R, W, TH, TE, TF, TG, Gg, and Ng[4]

  • Sibiricose A1, sibiricose A5, and sibitircose A6 (acetylated sucrose molecules)[4][18]

  • 7-O-methylmangiferin, shibiricaxanthone A, and lancerin (xanthones)[4]

  • Yuanzhi-1 (pentacyclic triterpenoid)[19] and tetrahydrocolumbamine (ethanolic extract[20][10]) as potential receptor ligands

  • Various triterpenoid glycosides[21]

  • Clionasterol[22] and variants such as ethyl cholestan-22-en-3-ol,[22]3-O-β-D-glucosyl ethyl cholestan-22-en-3-ol, and 3-O-β-D-glucopyranosyl clionasterol (ethanol acetate fraction[23][22])

  • Chondrillasterol and 3β-O-β-Pyranoglucosyl Chondrillasterol[23]

  • Poligapolide (macrolide with the structure of (9R)-(−)-9-peptandecanolide[23])

  • Watterrose I, Fallaxose C, and Reniose A[6]

  • Phenyl propanoids including 3,4,5-trimethoxy methyl cinamate[23] and 3,4,5-trimethyoxycinnamic acid,[24] with the latter at 1.02+/-0.03mg/g in the water extract of the roots[25]

  • Xanthones including 1,2,3-Trihydroxy-6,7-dimethoxy xanthone, 1,2,3,6,7-Pentahydroxy xanthone, and 6-Hydroxy-1,2,3,7-tetramethoxy xanthone[23]

  • Sterols including 3α-O-β-Pyranoglucosyl spinasterol[23]

  • The flavonoid 3′,4′-Dimethoxy-7-diglucosyl-O-methylenoxy-5-hydroxyl flavol[23]

  • Two acidic polysaccharides[26] and an amine-containing polysaccharide,[27] with total polysaccharides comprising 5.27% of the root's dry weight[26][27]

While there are many possible bioactives in this plant, the ones that mediate its known effects include the saponins tenuigenin and yuanzhi-1. Most research to date has focused on the carbohydrates or 'acetylated oligosaccharides' which are known as tenuifolisides or tenuifolioses.

1.2. Sources and Structure

Major groups of molecules include acetylated sucrose (the tenuifolisides, shibiricoses, and DISS, which are a sugar molecule acetylated with select phenolics, and the tenuifoliose series, which are larger carbohydrate structures consisting of five sugar molecules which also differ based on the phenolics bound to the carbohydrate backbone.[4] Most other molecules in this plant are either xanthone in structure or triterpenoids (tenuigenin and onjisaponins), while the acetylated carbohydrates are thought to either act inherently or act as prodrugs for the phenolics they are bound to such as sinapic acid.[4]

The root of this herb appears to contain two major classes of molecules: triterpenoids, which appear unique to this plant, and small carbohydrates (2-5 sugars in length) that are bound to a large amount of small phenolic structures such as p-coumaric acid or sinapic acid.

1.3. Variants and Formulations

A standardized ethanolic root extract of Polygala tenuifolia known as BT-11[24] has been used in cognitive studies in humans.[28][29]

Ethanolic extracts are enriched in acetylated oligosaccharides, with a 30% ethanolic extract in one study containing 44.88% acetylated sucrose molecules (DISS, tenuifolisides, and sibiricoses).[18] In another study, ethanolic extraction (sequential elutions of water, 30% ethanol, and finally 95% ethanol) resulted in a product enriched with tenuifolin and low weight phenolic acids.[30]

BT-11 is a standardized ethanolic root extract used in the human studies. Ethanolic extracts of this plant are efficient in increasing the relative concentration of the acetylated oligosaccharides that are likely some of the major bioactives found in the root.

Kampo (traditional Japanese) medicine uses a few plant formulations that contain Polygala tenuifolia including:

  • Kami-kihi-to using 2.0 grams of polygalae radix (root of Polygala tenuifolia) alongside the roots of Angelica acutiloba (2.0g), the roots of Astragalus membranaceus (3.0g), the roots of Atractylodes lancea (3.0g), the root of Bupleurum falcatum (3.0g), the fruits of Gardenia jasminoides (2.0g), the roots of Panax ginseng (3.0g), Licorice roots (1.0g), the sclerotium of Poria cocos (3.0g), the aril of Dimocarpus longan (3.0g), the root of Saussurea lappa (1.0g), Ginger root (1.0g), Ziziphus jujuba fruits at 2.0g and their seeds at 3.0g[3]

  • Ninjin-yoei-to with 4.0 grams of each Rehmannia glutinosa root, Poria cocos sclerotium, Atractylodes japonica root, and Angelica acutiloba, 3.0 grams Panax ginseng, 2.5 grams Cinnamon (Cassia), 2.0 grams of each Polygalae radix, Paeonia lactiflora, and Citris unshiu peel and lesser amounts of Astragalus membranaceus (1.5g), Schisandra chinensis (1.0g), and licorice (1.0g)[3]

  • Kami-untan-to which is predominately Pinellia ternate tuber (5.0g) with 3.0 grams of each Citrus aurantium (bitter orange fruit), Citris unshiu peel, Poria cocos sclerotium, and Phyllostachys nigra stalk with 2.0 grams of each Panax ginseng, licorice, Polygalae radix, Rehmannia glutinosa root, Scrophularia ningpoensis, and both Xiziphus jujuba fruits and seeds while having 0.5 grams of ginger[3]

  • Kai Xin San which is an ethanolic extract containing 1.5 parts both Panax ginseng and Wolfiporia cocos to one part both Polygala tenuifolia and Acorus gramineus[31]

There are a few formulations in both Chinese and Japanese traditional medicine which use the roots of Polygala tenuifolia alongside other herbs, usually for cognition-related purposes.

2Molecular Targets

2.1. PI3K/Akt

Poligapolide, a macrolide derived from Polygala tenuifolia roots, has been shown to have potent phosphoinositide 3-kinase (PI3K)/Akt inhibitory activity. When a microglial cell line was transduced with the HIV-1-TAT peptide that causes constitutive activation of PI3K signaling via suppression of PTEN expression, poligapolide inhibited PI3K signaling with a potency comparable to miltefosine when tested at 20µM.[32] As expected, this suppressed downstream Akt and glycogen synthase kinase-3β signaling, although signaling via PI3K (to pyruvate dehydrogenase lipoamide kinase isozyme 1) was preserved.[23] Other xanthones and sterols showed similar inhibitory actions on PI3K/Akt signaling but with lesser potency. [23] Clionosterol and its structural analogs have shown similar PI3K inhibitory activity; both clionosterol and cholestan-2-enol are comparable to miltefosine, inhibiting PI3K in a concentration-dependent manner between 5-20µM.[22]

Tenuifoliside A has also shown that its ability to increase brain-derived neurotrophic factor (BDNF) levels in the brain are dependent on PI3K activation.[2]

Some components of Polygala tenuifolia appear to be PI3K activators, without having any influence on Akt.


3.1. Absorption

In rats, 3,6'-disinapoylsucrose (DISS, a major active component of Yuan Zhi) exhibited poor absorption, with a bioavailability of approximately 0.5%.[33] The low bioavailability of DISS has been attributed to low cell permeability and a lack of active transporter-mediated uptake, instead being absorbed by a passive, paracellular mechanism.[34] Nevertheless it can be absorbed; a water extract of Polygala tenuifolia dosed at 1.56 g/kg in rats led to detection of DISS and two other acetylated sucrose molecules (sibiricose A5 and A6) in the serum one hour after ingestion,[18] and 50 mg/kg pure DISS has shown a Tmax of 30 minutes reaching a Cmax of 16.2+/-2.9 ng/mL with a half life of 26.9+/-7.8 minutes.[33]

Coincubation with sodium caprate, an agent known to increase paracellular absorption,[35] has been shown to increase the absorption of DISS both in vitro (in a Caco-2 cell model) and in situ (in the rat during intestinal perfusion).[34] The Kampo formulation known as Kami-kihi-to may also have increased DISS bioavailability due to inclusion of Chinese Licorice[3] which contains 18β-glycyrrhetinic acid, an agent known to increase paracellular nutrient absorption.[36]

Oligosaccharide esters in Polygala tenuifolia_ such as DISS are poorly absorbed in the intestines due to low cell membrane permeability and absorption via a passive, paracellular mechanism. Bioavailability can be increased with agents that enhance paracellular absorption such as sodium caproate or licorice.

3.2. Distribution

After an oral ingestion of 10g/kg Polygala tenuifolia water extract, a few intact molecules found in the roots of the plant were detected in the serum of rats over the course of the next eight hours, with polygalasaponin XXXII and 3,6'-disinapoylsucrose (DISS) being most representative.[4] Other detected intact molecules including tenuifolisides A, I, and H as well as senegin III.[4] Two glucuronide metabolites (shibiricoses A5 and tenuifoliside B) were also detected.[4]

3.3. Elimination

When rats were fed a high dose (10g/kg) of a water extract of Yuan Zhi roots, urine analysis over the course of eight hours revealed the presence of oligosaccharides such as tenuifoliside B and sibiricoses that were glucuronidated.[4] Urinary xanthones such as 6-hydroxy-1,2,3,7-tetramethoxyxanthone were also detected and subject to glucuronidation.[4]

After ingestion of Polygala tenuifolia, various glucuronidated metabolites are detected in plasma and urine.


4.1. Adenosinergic Neurotransmission

An 80% ethanolic extract of Polygala tenuifolia roots injected intraperitoneally to mice at the doses of 25 and 50mg/kg every other day for a week has been noted to attenuate locomotion induced by cocaine in a manner dependent on the A2A adenosine receptor, independent of the adenosine A2B and A1 receptors.[10]

Injections of Polygala tenuifolia root extracts activate the adenosine-signaling system via the adenosine A2A receptor. It is not clear whether this also occurs through oral administration.

4.2. Adrenergic Neurotransmission

In aged mice experiencing an age-related decreases in hippocampal noradrenaline concentrations oral administration of tenuifolin (40 or 80mg/kg) restored noradrenaline to levels comparable to a youthful control group.[7] Importantly, the tenuifolin-induced increase in noradrenaline levels was also associated with improvements in learning and memory.

Polygala tenuifolia has been shown to improve learning and memory in aging mice by preventing reductions in brain neurotransmitter levels including noradrenaline.

The triterpenoid yuanzhi-1 is a potent noradrenaline transporter (NAT) antagonist. In vitro assays demonstrated that yuanzhi-1 interacts with this receptor with high affinity, displacing that standard selective NAT inhibitor nisoxetine by 59% at concentrations of 1nM and 78% at 100nM.[19] Yuanzhi-1 did not appear to interact with adrenergic receptors at these concentrations, since its affinity was in the micromolar range for the β1 receptor (IC50 of 3.7µM) and α2A (4.2µM). Yuanzhi-1 concentrations up to 10µM failed to interact with α1A and α2B.[19]

Yuanzhi-1, a minor constituent of Polygala tenuifolia, is a potent noradrenaline transporter inhibitor.

4.3. Cholinergic Neurotransmission

Oral ingestion of tenuifoliside B (3 and 10mg/kg with equal efficacy) in mice has been noted to increase oxotremorine-induced tremors with similar potency on a per-weight basis to tacrine (10mg/kg), a muscarinic choline agonist.[3]

Tenuifolisde B stimulates the cholinergic system with similar potency to tacrine on a per-weight basis.

The Kampo formulation kami-untan-to has been noted to increase choline acetyltransferase (ChAT,an enzyme involved in acetylcholine synthesis) activity in vitro[37][38] and in rats.[38] This effect of kami-untan-to has been specifically traced back to to Polygala tenuifolia root extracts, with 12.5-50μg/mL being effective at enhancing ChAT activity.[39] Maximal stimulation of ChAT activity occured 25μg/mL, resulting in a 50% increase over basal levels.[39] The specific components of the root extract affecting ChAT seem to be the onjisaponins, as onjisaponin F has shown efficacy at inducing ChAT at 1μg/mL and 10μg/mL.[40]

ChAT activity was later noted to increase by 30% in rats fed 500mg/kg of a Polygala tenuifolia root extract for one week, with 100mg/kg being ineffective. 100mg/kg of pure sinapic acid (a metabolite of Polygala tenuifolia saccharides) increased ChAT activity to a similar degree.[39]

The formation of acetylcholine from choline within a neuron appears to be increased following incubation of neurons with Polygala tenuifolia root extract in vitro. This effect has also been noted to occur after oral ingestion of a high (yet reasonable) dose of the root. A few different compounds isolated from Polygala tenuifolia have been associated with this effect.

100-200mg/kg of a 9:1 ethanol:water Polygala tenuifolia root extract reduced acetylcholinesterase (AChE) activity in aging rats.[41] BT-11 (80% ethanolic root extract) has also shown noncompetitive inhibitory actions on AchE in vitro, with an IC50 of 263.7µg/mL.[42]

Tenuifolin in isolation at 20-80mg/kg has shown an ability to reduce cortical AChE activity in aged mice following 15 days oral administration.[7]

Ethanolic root extracts of Polygala tenuifolia reduce acetylcholinesterase activity at high concentrations. Isolated tenuifolin has increased potency relative to crude root extracts, showing similar effects at much lower concentrations.

4.4. Dopaminergic Neurotransmission

One study involving oral administration of tenuifolin (20-80mg/kg) for 15 days in aged mice that experienced an age-related decrease in dopamine concentrations of the hippocampus noted that the two higher doses (40 and 80mg/kg) were able to normalize dopamine levels to levels similar to a youthful control group.[7]

Similar to noradrenaline, mouse evidence suggests that the decrease in dopamine seen in the aging brain appears to be attenuated with supplementation of Polygala tenuifolia with no evidence yet available for otherwise healthy youthful brains.

Yuanzhi-1 has affinity for the dopamine transporter at a concentration range of 1-100nM, while having comparatively weaker affinity for the receptors.[19] It was able to bind to D1 (IC50 3.4µM), D3 (3µM) and D4 (2µM) while concentrations of up to 10µM failed to interact with D2 or D5.[19] Another minor component of the root (tetrahydrocolumbamine) seems to have affinity for D1 (IC50 of 750nM) and D2 (920nM)[20] and while a collection of polygalasaponins given to rats has been associated with antidopaminergic activity as assessed by apomorphine-induced climbing tests[43] the minimum effective dose for the polygalasaponins was 250mg/kg (40mg/kg estimated human equivalent) and may be too high to be relevant to supplementation.

The minor constituent yuanzhi-1 has potent affinity towards the dopamine transporter, although its effects are not yet confirmed.

4.5. Glutaminergic Neurotransmission

In studies assessing NMDA-induced neuronal death, Polygala tenuifolia root extract has shown protective effects in the concentration range of 50ng/mL to 5μg/mL in cerebellar granule cells.[44] At a concentration of 500ng/mL, it also reduced the NMDA-induced release of glutamate, which mitigated glutamate-induced excitotoxicity.[44]

Polygala tenuifolia appears to inhibit NMDA-induced excitotoxicity at very low concentrations in vitro.

The GluR1 subunit of AMPA in rats has been noted to have reduced phosphorylation at Ser-845 30 minutes following oral ingestion of 0.1mg/kg Polygala tenuifolia root which appears to be involved in its antidepressant effects in mice.[8]

The antidepressant effects of Polygala tenuifolia extract (0.1mg/kg oral ingestion in mice) is abolished when AMPA is blocked.[8] This is known to occur with any antidepressant which works via NMDA antagonism such as ketamine or MGS0039.[45][46] Since AMPA blockade does not prevent the effect monoaminergic antidepressants,[47] this suggests that the effect of Polygala tenuifolia on depression is mediated by antiglutaminergic activity.[8] Unlike ketamine, however, Polygala tenuifolia does not activate hippocampal mTOR in neurons,[8] which may (disputably[48]) play a role in NMDA antagonists' antidepressive effects.[49]

A similar antidepressive effect has been noted in rats with pure 3,6'-disinapoylsucrose (DISS) at oral doses of 5-20mg/kg. In this case 10-20mg/kg DISS were equipotent to 10mg/kg fluoxetine, suggesting that DISS is the active component.[50]

AMPA also appears to be involved in the rapid onset antidepressant effects of Polygala tenuifolia, and blocking AMPA will block the antidepressant effects mediated by NMDA inhibition. These effects may be caused by the DISS content of Polygala tenuifolia.

Isolated components of Polygala tenuifolia have demonstrated some proglutaminergic activity, such as polygalasaponin F (intracerebroventricular injection of 1-10µM) activating NMDA in the hippocampus[14] and senegenin (15-60mg/kg oral) increasing NR2B mRNA and protein expression in the same brain region in rats subject to cognitive deficit.[13]

Some triterpenoids have shown proglutaminergic activity when tested in isolation although these effects have not been observed with whole root extract.

4.6. Serotonergic Neurotransmission

Unlike its effects on dopamine and noradrenaline in the aging mouse hippocampus, oral supplementation of 20-80mg/kg tenuifolin failed to influence the age-related decline of serotonin in this brain region over the course of 15 days of supplementation.[7]

The age-related decrease in serotonin does not appear to be attenuated with supplementation of Polygala tenuifolia root extract according to mouse data.

Yuanzhi-1 has been noted to bind to and inhibit the serotonin transporter (SERT) with high affinity, outcompeting ligands at a concentration of 1nM (62%) and 100nM (95%). Notably, it has not been shown to bind any serotonin receptors in the nanomolar range, although it does interact with several with micromolar affinities: 5-HT1A (IC50 of 3µM), 5-HT1B (4µM), 5-HT2A (4.2µM) and 5-HT7 (5.3µM). 5-HT1D, 5-HT2C, 5-HT3, 5-HT5A, and 5-HT6 were not influenced at concentrations below 10µM Another triterpenoid (yuanzhi-3) had some efficacy at 100nM on binding to SERT (43%). The potency of yuanzhi-1 appears to be comparable to fluoxetine.[19]

A mixture of polygalasaponins from polygala tenuifolia has been noted have anti-serotonergic effects when 50mg/kg of the polygalasaponins is injected prior to serotonin syndrome (induced by excessive levels of 5-HTP)[43] although the relevance of this mechanism to oral supplementation of the herb is uncertain.

Yuanzhi-1 appears to have similar affinity to the serotonin transporter as the reference SSRI fluoxetine. Interaction with serotonin receptors requires at least 30-fold higher concentrations.

4.7. Miscellanous Mechanisms

Aging mice treated with 100-200mg/kg, but not 50mg/kg, of a 9:1 ethanol:water Polygala tenuifolia root extract for four weeks had reduced total monoamine oxidase (MAO) activity relative to controls. In this case, the Polygala tenuifolia extract suppressed MAO with a potency comparable to 3mg/kg galantamine.[41] Another study in rats found that 10-20mg/kg of 3,6'-disinapoylsucrose (DISS) suppressed the stress-induced increase of both MAO-A (31.8-32.9%) and MAO-B (25.5-35.6%) with similar potency to 10mg/kg fluoxetine.[50]

MAO activity is decreased with both Polygala tenuifoliaroot extract and isolated DISS in animal models.

One component of Polygala tenuifolia known as yuanzhi-1 has been noted to bind to and inhibit serotonin, noradrenaline, and dopamine transporters at a concentration of 1nM and exerted antidepressant effects in the mouse at a minimum dose of 2.5mg/kg.[19] This suggests that yuanzhi-1 may be a selective triple monoamine reuptake inhibitor, as it failed to bind to any other tested targets aside from these three transporters.[19]

Yuanzhi-1 appears to be a relatively selective monoamine transporter inhibitor.

4.8. Bioenergetics

One study in using BT-11 (10mg/kg oral ingestion) or 10mg/kg 3,4,5-trimethoxycinnamic acid isolated from Polygala tenuifolia for two weeks in rats exposed to chronic (restraint) stress noted that decreases in glucose utilization observed with stress in a few brain regions (olfactory bulbs, cerebral cortices, thalami, and cerebrella) were reversed.[24]

In rats exposed to chronic stress, the reduction in glucose utilization expected from the stress was reduced by BT-11 treatment.

4.9. Neurogenesis

Polygala tenuifolia has been noted to increase nerve growth factor (NGF) secretion when incubated with astroglial cells in the concentration range of 12.5-50μg/mL,[40][39] with most efficacy occurring at a concentration of 25μg/mL.[39] This may be mediated by the onjisaponins (mostly onjisaponins F and G) from the root, which increased NGF secretion in the range of 0.1-10μg/mL.[40]

Polygala tenuifolia root extract increases the secretion of NGF in cultured astroglial cells. It is currently unknown whether this occurs in vivo.

3,6'-disinapoylsucrose (30-200μM; most potent at 60μM) has been noted to have protective effects against H2O2in vitro via increasing brain-derived neurotrophic factor (BDNF) secretion. This was mediated by CaMKII, ERK1/2, and TrkB, but not PI3K or PKA, signaling.[5] Polygalasaponin XXXII at a low oral dose (2mg/kg) in mice has also shown protective effects against memory loss (induced by scopolamine) with a potency comparable to 0.05mg/kg Huperzine-A.[17] This was due to increased BDNF in the hippocampus and was replicated in vitro at a concentration of 1μM, where ERK and CREB (downstream of BDNF) were activated within four minutes.[17] Tenuifoliside A has also shown BDNF-releasing properties in vitro in a manner dependent on PI3K/ERK activation.[2]

Several individual components of Polygala tenuifolia have been noted to either directly increase BDNF secretion (via PI3K/ERK signaling) or to otherwise preserve BDNF in instances where it would normally be reduced (such as scopolamine-induced amnesia).

When tested in vitro, tenuigenin activated the proliferation and differentiation of hippocampal stem cells in the concentration range of 1-4μg/mL over eight days of incubation.[51] Importantly, hippocampal stem cells are present in the adult mammalian brain and can be differentiated into mature neurons,[52][53] suggesting that Polygala tenuifolia could have a positive effect on neurogenesis. Tenuigenin induced differentiation of these stem cells into both astrocytes and neurons.[51] In addition to its effect on neurogenesis, tenuigenin in the range of 2-4μg/mL has been shown to protect hippocampal cells from damage in vitro from a toxic metabolite of glucose often seen in patients with diabetes.[54]

In mice with ovariectomy (an animal model of menopause-related cognitive decline), oral ingestion of 4mg/kg tenuigenin twice daily for four weeks was able to prevent memory losses associated with attenuating changes in synaptic density and the size of the active zones.[11] When this dosing regimen was given to otherwise healthy mice, increased synaptic plasticity was noted in the hippocampus. Direct perfusion (2μg/mL) enhanced field excitatory postsynaptic potential both in basic synaptic transmission and after high frequency stimulation.[55]

Oral administration of tenuigenin appears to increase hippocampal activity in otherwise healthy mice, while in models of cognitive deficit there appears to be a preserving effect on hippocampal transmission.

4.10. Neuroprotection

An oligosaccharide found in the roots of Polygala tenuifolia known as tenuifolisde B (3-10mg/kg oral ingestion), has been noted to confer protection against KCN-induced anoxia and scopolamine-induced amnesia inmice with more potency than an equal dose of tacrine (3-10mg/kg), to such a degree where 10mg/kg of tenuifoliside B improved performance in a passive avoidance test relative to control despite scopolamine.[3] Tenuifoliside A and other oligosaccharide esters such as 3,6'disinapoylsucrose (DISS) also possess a neuroprotective effect in vitro, reducing damage from corticosterone on SY5Y neuroblastoma cells, with peak efficacy at 150µM and 15µM, respectively.[56]

4.11. Neuroinflammation

The aerial parts of Polygala tenuifolia have been noted to have antiinflammatory effects in microglial cells exposed to lipopolysaccharide (LPS), with four compounds from the plant having IC50 values in the range of 16.2-38.5µM and the most effective having an IC50 of 7.4µM.[57]

The water extract of the root has these properties to a more potent degree, with 8µg/mL halving nitric oxide and PGE2 production according to one study[58] and another noting that a water extract at a concentration of 10µg/mL almost completely prevented TNFα secretion induced by LPS.[59] Inhibition of NF-kB translocation by preventing IκBα degradation was also noted,[58] which, if similar to Polygala tenuifolia actions in macrophages, was due to JNK inhibition.[60] It is uncertain which compounds are active in the water extract of the root, although tested xanthones and phenolic acids have had IC50 values in between 10-100µM.[61]

The water extract of Polygala tenuifolia root appears to have antiinflammatory effects in microglial cells in vitro.

4.12. Sedation

Studies assessing the antidepressant effects of Polygala tenuifolia have noted that high doses (100mg/kg of the root) have caused sedation in mice,[8] which may be related to the polgalasaponin content, as they have shown sedative and hypnotic effects when tested in isolation at higher-than-normal oral doses (40-160mg/kg).[62] Studies using the minimum dose for antidepressant effects (0.1 mg/kg), however, haved failed to note any alterations in locomotion relative to control groups.[8]

Higher-than-normal doses of Polygala tenuifolia root extracts appear to have sedative properties which is thought to be related to the triterpenoid component.

4.13. Anxiety and Stress

A few rat models assessing the effects of Polygala tenuifolia root have used a model for stress known as chronic mild stress (CMS), designed to assess the effects of chronic rather than acute stress, a type of stress known to affect BDNF concentrations.[63] When using this model, 3,6'-disinapoylsucrose (DISS) has shown a cortisol-reducing effect,[50][64] with 10-20mg/kg DISS being comparable to 10mg/kg fluoxetine in potency.[50] Antidepressant activity was also seen, associated with a preservation of BDNF mRNA when DISS was administered orally at 5-20mg/kg.[65]A Polygala tenuifolia extract yielded similar results.[66]

DISS or Polygala tenuifolia extract may confer adaptogenic effects in the rat exposed to chronic mild stress. DISS has a potency similar to fluoxetine in rats in this model of stress.

4.14. Depression

Polygala tenuifolia is known to have antidepressant properties in rodents, which is likely related to its actions at NMDA receptors. Blockade of NMDA signalling causes rapid antidepressant effects[48] most commonly seen with the drug ketamine,[67] although the psychoactive effects of ketamine and its potential for abuse prevent widestream use.[68]

Extract from the root of Polygala tenuifolia can hinder NMDA receptor signalling,[44]presumbably via sinapic acid or prodrugs like 3,6'-disinapoylsucrose (DISS),[50]which also promote this rapidly-acting antidepressive effect in rats.[66][8] 0.1mg/kg of the root has been noted to have potency comparable to 10mg/kg IV ketamine in mice.[8] As might be expected, higher doses (100mg/kg) of the root has caused sedation.[8]

The fast acting antidepressive effects of Polygala tenuifolia that have been noted in rodents appear to be similar in mechanism and potency to ketamine, a known NMDA antagonist with rapid-acting antidepressive effects.

4.15. Memory and Learning

One study assessing the neuroprotective effects of Polygala tenuifolia in mice found that one component, the oligosaccharide tenuifoliside B, exerted protective effects against scopolamine in a passive-avoidance task in a dose-dependent manner. Oral dosage in the range of 3-10mg/kg proved effective in this work, with 10mg/kg not only fully preventing amnesia but also improving performance relative to control.[3] The ethanolic root extract BT-11 has been noted to have similar effects when injected at 10mg/kg.[42] Moreover, oral ingestion of tenuifolin at a dose of 40-80mg/kg has shown protective effects on memory impaired by scopolamine, sodium nitrite (20-80mg/kg), and Alcohol (80mg/kg only).[7] Tenuigenin is another saponin specifically implicated in cognitive enhancement in mice, where 4mg/kg prevented cognitive dysfunction in animals subjected to ovariectomy with a potency comparable to estradiol.[11] Importantly, the effects of tenuigenin are not limited to hormone-compromised mice, as the same 4mg/kg dose improved learning and memory in otherwise healthy mice by enhancing synaptic plasticity.[55]

Stress-induced memory deficits appear to be attenuated with 10mg/kg oral ingestion of BT-11 (80% ethanolic extract of the roots) in rats exposed to two weeks of restraint stress.[24]

A dried root extract of Polygala tenuifolia given orally to aging mice at doses of 50-200mg/kg for four weeks alongside testing caused a time- and dose-dependent improvement in cognition associated with the two higher doses (100 and 200mg/kg), with 100mg/kg comparable in efficacy to 3mg/kg galantamine.[41] This enhancement was not accompanied by alterations in locomotion, and increased antioxidant enzyme activity (SOD and CAT) was noted along with with a decrease in monoamine oxidase (MAO) activity comparable to galantamine. Acetylcholinesterase(AChE) activity was reduced to a lesser extent relative to galantamine.[41] In otherwise healthy rats, an oral dose of 4mg/kg pure tenuigenin was noted to increase SOD activity in the hippocampus alongside a reduction in acetylcholinesterase (AChE) activity, resulting in improved memory and learning performance (Y-maze).[55]

In rodent models of memory impairment or age-related memory loss, oral ingestion of Polygala tenuifolia appears to have potent protective effects resulting in improved memory.

In otherwise healthy middle-aged adults 100mg BT-11 thrice daily over the course of four weeks improved immediate word recall relative to placebo, although both short and long term recall improvements (free and cued) assessed by the Korean version of the California Verbal Learning Test (K-CVLT) were not significant.[28] While there were no between-group differences in recognition scores, there was a significant increase in BT-11 treated patients relative to placebo.[28] In a spatial test for working and strategic memory (SOPT) there was a significant improvement noted with BT-11, with a 19% reduction in errors relative to placebo.[28]

In elderly adults given the same dose of BT-11 for eight weeks, supplementation showed benefits in total Consortium to Establish a Registry for Alzheimer's Disease Assessment Packet (CERAD) scores, word list learning, and constructional measures (recall and praxis). In contrast, benefits to other parameters such as total MMSE scores, verbal fluency, and recognition did not reach significance and word list recall failed to improve with supplementation.[29]

One study in otherwise healthy middle-aged humans suggests that BT-11 may have possible memory-promoting effects according to some submeasures of verbal learning, although no overall difference was noted relative to placebo groups. Another study in the elderly also found that BT-11 may improve cognitive function by some measures, although again the benefits did not manifest across all measures.

5Inflammation and Immunology

5.1. Macrophages

Tenuifoliside A has been shown to have potent antiinflammatory properties in lipopolysaccharide-stimulated macrophages, attenuating Nitric Oxide, TNF-α, and PGE2 production in a concentration-dependent manner between 5-40µM. Suppression of these inflammatory mediators occurred via inhibition of JNK signaling, which prevented nuclear translocation of NF-kB and activation of pro-inflammatory gene expression.[60]

Tenuifoliside A, a phenylpropanoid isolated from Polygala tenuifolia has been shown to have potent anti-inflammatory properties in macrophages, suggesting that it may be useful for the treatment of inflammatory disorders.

5.2. Virology

Some components of Polygala tenuifolia (onjisaponins) have been found to function as potent adjuvants, potentiating the immune response to vaccines by increasing antibody production. When mice were vaccinated against influenza, Polygala tenuifolia increased antibody production by 27-50 fold compared to vaccination alone.[69] This effect was not limited to influenza vaccination, as this onjisaponin also increased IgA and IgG concentrations when co-administered with a diphtheria-pertussis-tetanus (DPT) vaccination.[69]

Polygala tenuifolia may function as as a potent natural adjuvant in mice, increasing antibody production when co-administered with a vaccine.

6Interactions with Hormones

6.1. Corticosteroids

The stress-induced increase in cortisol observed in rats following chronic mild stress (CMS) testing was reduced with oral ingestion of 3,6'-disinapoylsucrose (DISS) in a dose-dependent manner, with DISS attenuating stress-induced cortisol by 28% at 5mg/kg and 57% at 20mg/kg. Although clearly effective in the doses tested, DISS-suppression of cortisol release was less robust that 10mg/kg fluoxetine, which attenuated cortisol production by 81%.[50]

The potential adaptogenic properties of Polygala tenuifolia seem to be traced back to the DISS content, where stress-induced increase in cortisol is partially suppressed in rats. Notably, this is an oral dose in the range that may achieved with supplementation of the root.

7Interactions with Oxidation

7.1. Superoxide

Oligosaccharides from Polygala tenuifolia have been shown to have potent antioxidant activity. Both 3,6'-disinapoylsucrose (DISS; 50mg/kg) or lower doses of an ethanolic extract (25-50mg/kg) increased superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) enzyme activity, restoring enzyme activity levels in senesence-accelerated mice comparable to those of normal controls.[6] Increased antioxidant activity also correlated with reduced lipid peroxidation in serum and liver in this model.[6] Similar results have been noted in brain tissue of normally-aging mice.[41]

The SOD-activity increasing effects of Polygala tenuifolia suggest that it may be particularly useful for certain instances of cognitive dysfunction (aging, chronic mild stress, or introduction of a research toxin), where decreased SOD results in increased lipid peroxidation.[41][50] Along those lines, triterpenoid tenuigenin also increased SOD activity in normal mice at 4mg/kg, enhancing synaptic plasticity.[55] Moreover, polygalasaponins isolated from Polygala tenuifolia have also been shown to preserve SOD activity in amnesiac mice.[30]

In addition to the increasing SOD activity, mouse studies have shown that Polygala tenuifolia also confers increased protection from oxidative stress by increasing catalase (CAT)[41] and glutathione peroxidase (GSH-PX)[6] activity.

Oligosaccharide esters isolated from Polygala tenuifolia have been shown to increase superoxide dismutase (SOD) in mouse models of aging and amnesia. Additional rodent studies indicate that triterpenoids from Polygala tenuifolia may also possess an inherent ability to increase SOD activity in the brain following oral ingestion.

8Interactions with Organ Systems

8.1. Liver

Polygala tenuifolia ethanolic root extract has been shown to activate peroxisome proliferator response element (PPRE) activity in Sk-hep1 liver cells in a concentration dependent manner at 100 µg/mL or above, suggesting that it may promote fatty acid oxidation.[70] Curiously, this same extract promoted lipid accumulation a medium containing Alcohol (to promote lipid accumulation) as assessed by Nile red staining,[70] suggesting that Polygala tenuifolia may actually promote lipid accumulation in vitro through unknown mechanisms.

Although ethanolic extracts of Polygala tenuifolia appear to activate anti-lipogenic signaling pathways, these same extracts have been shown to promote lipid accumulation in liver cells in vitro. Thus, more research is needed to ascertain the effects of Polygala tenuifolia on lipogenesis.

9Interactions with Cancer Metabolism

9.1. Lung

Two purified polysaccharides from a hot water extraction of Polygala tenuifolia (5.27% dry weight of the root) have demonstrated potent cytotoxic, anti-proliferative effects in A549 lung adenocarcinoma cells, with IC50 values between 41.2-47.8 µg/mL. When these cells were injected into 'nude' mice with suppressed immune systems to create tumors, intraperitoneal (IP) injection of either polysaccharide at doses in the range of 50-100 mg/kg also showed potent anti-tumor activity.[26] These polysaccharides were also effective in vitro, with cyto-toxic, anti-proliferative effects in MCF7 breast cancer cells (IC50 values of 65.9-67.2 µg/mL) and HT-29 colon carcinoma cells (71.4-78.3 µg/mL). Only one of the polysaccharides showed cyotoxicity in HepG2 liver carcinoma cells below 100 µg/mL (83.2µg/mL), and neuroblastoma cells were unaffected by either polysaccharide at concentrations below 100 µg/mL.[26]

Polysaccharides isolated from Polygala tenuifolia have shown cytotoxic effects in several cancer cell lines, with the most potent effects against a lung adenocarcinoma line. This suggests that extracts from Polygala tenuifolia might be useful for the development of new drugs to target certain types of cancer.

9.2. Ovarian

A water-soluble polysaccharide from the roots of Polygala tenuifolia has also been noted to have antiproliferative properties in ovarian (SKOV3) cancer cells in a concentration-dependent manner between 10-40µg/mL. Similar effects were noted in nude mice bearing SKOV3 cells with 10-40mg/kg IP injections of the polysaccharide.[27] Similar effects have been seen in vitro in a human ovarian cancer cell line, where polysaccharide downregulated telomerase activity in these cells as well as decreased expression of the proto-oncogene Bmi-1.[71] The polysaccharide can also induce apoptosis through the mitochondrial pathway in these cells.[72]

10Sexuality and Pregnancy

10.1. Seminal Properties

High concentrations of water extract from Polygala tenuifolia applied directly to semen appears to possess rapid-acting spermicidal properties, with 10-20mg/mL causing absolute immobilization and lysis of all sperm cells and 5mg/mL immobilizing 39.5+/-3.2% of sperm.[73]

Polygala tenuifolia has potent spermicidal effects when applied directly to sperm. There are currently no studies assessing the effects of oral ingestion on fertility, which is not known.

11Interactions with Medical Conditions

11.1. Alzheimer's Disease

A hallmark of Alzheimer’s disease (AD) is the secretion of amyloid beta peptide Aβ, which forms toxic plaques in the brains of AD patients.[74] The saponin tenuigenin (from an ethanolic Polygala tenuifolia root extract) has been noted to reduce secretion of amyloid β-protein (Aβ) in neuroblastoma cells.[12] 1 µg/mL of tenuigenin reduced Aβ secretion to 75% of baseline, while 2-4 µg/mL were equipotent in reducing secretion to approximately 30% of baseline, with total amyloid precursor protein (APP) content unaffected.[12] Tenuigenin was found to reduce Aβ levels by inhibiting β-secretase 1 (BACE1), an enzyme that plays a role in the processing of APP into Aβ through proteolytic cleavage. Tenuigenin inhibited BACE1 in a concentration-dependent manner, with an IC50 of 250 ng/mL.[12] Tenuifolin, a metabolite of tenuigenin, has also been shown to inhibit BACE1 (54.4% inhibition at 10 µg/mL and 39.3% at 1 µg/mL) and reduce Aβ efflux from neurons.[9]

When rat neurons were treated with Aβ, the BT-11 extract (3-5 µg/mL but not 500 ng/mL) prevented amyloid protein cytotoxicity over the course of a 12 hour incubation period.[42]

Polygala tenuifolia has also demonstrated neuroprotective effects in mouse models, where hydrolysates of polygalasaponins reduced Aβ-induced amnesia in mice (50-100mg/kg oral ingestion), which was associated with an increase in superoxide dismutase (SOD) antioxidant activity.[30]

A hallmark of Alzheimer’s disease is the secretion of amyloid beta peptide Aβ, which forms toxic plaques in the brains of AD patients. Aβ is produced in part via proteolytic cleavage of the amyloid precursor protein by the enzyme BACE1. Tenuigenin (obtained from Polygala tenuifolia root extracts) is a potent BACE1 inhibitor in vitro, reducing Aβ secretion in a number of in vitro models. Although no human trials have been conducted, a limited amount of animal studies suggest that Polygala tenuifolia extracts show potential for treatment of Alzheimer’s disease

11.2. Parkinson's

In PC12 cells treated with 6-OHDA to induce Parkinson's-like damage, the root extract of Polygala tenuifolia had protective effects in the concentration range of 50-1,000 ng/mL, with peak efficacy (around half of cells preserved relative to control) at 500ng/mL.[25] This protective effect was observed along with mild attenuations of Nitric Oxide and reactive oxygen species (ROS) production, as well as nearly complete inhibition of caspase-3 activation, a key enzyme for cellular apoptosis.[25]

Compounds in the root known to exert protective effects include polygalasaponin F (0.1-10μM) against rotenone[15] and tenuigenin (0.1-10μM) against 6-OHDA, with a lower concentration (100 nM) having mild protective effects in vitro and 10 μM fully-protecting neurons and preserving superoxide dismutase (SOD) activty.[75] Tenuigenin has also been noted in one study to indirectly protect dopaminergic neurons from inflammation induced by LPS in rats (acting via glial cells). Although it was highly effective in nearly abolishing alterations in cognition and inflammatory cytokines, it required a high oral dose (300mg/kg).[76]

Oral ingestion of the root extract in rats at 100 mg/kg for three days before administration of a Parkinson's-mimicking toxin (MPTP) reduced the number of tyrosine hydroxylase positive cells (a marker for neural toxicity). This occurred to a similar degree as 100 ng/mL root extract in vitro. Seven days after treatment of the toxin, the root extract reduced markers for neuronal damage in vivo by 71.5%.[25]

In rodents, low oral doses of Polygala tenuifolia appear to be protective against oxidative stressors modeling the development of Parkinson's disease. This effect may be related to the triterpenoid content of the root extract (tenuigenin and polygalasaponin F).

12Safety and Toxicology

12.1. General

BT-11 is reported to be safe in rats with doses of up to 600mg/kg, and the estimated maximum safe human dose (after a 100-fold safety factor is applied to the aforementioned rat dose post species conversion) is estimated to be 360mg for a 60kg human.[29][28] 300mg (100mg thrice daily) has been used in two studies, one involving elderly subjects for two months and one involving younger healthy volunteers for one month, and was generally well-tolerated;[29][28] no serious adverse events were reported in either study, although in the 23% of the elderly subjects reported mild dyspepsia which resolved after one month (versus 3% in the placebo group),[29] with similar results in the other trial (mild dyspepsia in 13% of the BT-11 group versus 4% in the placebo group).[28]

12.2. Case Studies

There has been a case report of a long-term worker in an herbal manufacturing plant developing Polygala tenuifolia-induced asthma and rhinitis presumably from long-term exposure to the herb; the allergic reaction to this specific plant was confirmed with a skin-prick test.[77]

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