Terminalia Arjuna

Terminalia arjuna (of the Combretaceae family) is a tree; a deciduous evergreen tree standing up to 20-30m above ground level.^[1] The bark of the tree appears to have medicinal properties, mostly touted to be a cardioprotective agent.^[2][3][4][5] It has been used in Ayurveda under the names of Arjuna, Dhavala, Kakubha, Kumbuk, Nadisarja, Veeravriksha, Partha, and Indradru.^[6][7] Other notable species in the Terminalia family include bellerica and chebula.^[8]

Beyond being used for its cardioprotective/cardiotonic abilities, Arjuna has also been reportedly used for genital health (leucorrhoea, Spermatorrhoea), urinary astringent, expectorant, and some aphrodisiac properties.^[7]

Traditional administration of Arjuna involves a decoction made with the bark and milk drank in the morning, or at least the powder of the tree bark; in the cases of fractures or contusions with echymosis, honey tends to be recommended.^[9] Usually 1-3g of the bark is used per day.^[10]

The tree bark, the main medicinal component, contains:

• The triterpenoids Arjunic acid and Arjunolic Acid,^[11][7] up to 3% and 1.5% (respectively) of an Ethyl acetate extract or 2% and 0.9% of a diethyl ester extraction. Minimal quantities (0.2-0.3% of each) in acetone, methanol, and ethanol extracts with a 60:40 ethanol:water extract reaching up to 0.72% and 0.48%, respectively.^[7] Arjunic acid has bioactive metabolites as well^[12]
• Arjugenin and Arjunetin,^[12] the former being an aglycone similar to Arjunic and Arjunolic Acids^[13]
• Arjunasides A-E (Triterpenoid monoglycosides)^[14] and Arjunetoside^[15]
• Ajunglycosides IV and V in the butanolic/methanolic fractions,^[16] also in the fruits of Terminalia chebula
• Arjunaphthanoloside, a napthanol glycoside^[17]
• Termiarjunoside I and II (Oleanane Glycosides),^[18] Terminoside A,^[19] and Terminolitin^[20]
• Pelargonidin, an anthocyanin^[21]
• The cardenolide 16,17-dihydroneridienone 3-O-beta-D-glucopyranosyl-(1->6)-O-beta-D-galactopyranoside^[22] and the structurally related xylopyranosyl(1->3)^[23]
• Ursane triterpenoids (2α,3β-dihydroxyurs-12,18-dien-28-oic acid 28-O-β-D-glucopyranosyl ester )^[24]
• Tannin structures (Gallic and Ellagic acids),^[25] 3-O-methylellagic acid 4′-O-α-L-rhamnopyranoside,^[24] Casuarinin,^[26] and Arjunin^[27]
• (-)-epicatechin^[24]
• Luteolin,^[25] Quercetin, Kaempferol and Baicalein^[21]
• Vitamin C at 1.47mg/100g (hydroalcoholic extract)^[1]
• Vitamin E at 0.58mg/100g (hydroalcoholic extract)^[1]

The three above triterpenoids are commonly seen as the main active ingredients, with other compounds with names related to this plant (Terminoside or Arjunoside as examples) tend to be glycosides of the three above aglycones. That being said, there is no evidence to support that these are the compounds that underlie the cardiovascular health properties although they appear to be causative of anti-cancer and anti-oxidative properties

And the fruits that the tree bears may contain:

• Arjunglucoside I-III and Arjunetin^[28]
• Hydrolyzable tannin structures (Ellagic acid, Gallic acid, Corilagin, Chebulagic acid, etc.)^[28]
• Chebuloside II and Bellericoside^[28]
• Dietary minerals of Calcium, Magnesium, Zinc, and Copper^[10]

Total phenolics may reach up to 8.05mg/100g in hydroalcoholic extracts of the bark; tannins may reach 5.1mg/100g.^[1]

In vitro, the water extract of Arjuna bark appears to have cardiotonic effects with 50ug/mL having similar potency (assessed via amplitude of CS (cell shortening), indicative of contractility) to 100nM Isoproteronol and 1mM Ouabain.^[25] The mechanism appears to be different, as a decrease in the decay time during relaxation was noted with both Isoproterenol and Arjuna (not with Ouabain) and both Arjuna and Ouabain (not Isoproterenol) caused an increase in the rise time during contraction.^[25] This was only observed with the water extract, with various organic extractions (ethanolic, ethyl acetate) causing varying effects and isolated Arjulinolic acid being arrhythmogenic (causing arrythmia).

Appears to have cardiotonic effects in vitro with isolated heart cells, seems to be associated with the water extract mostly

One month of treatment of 500mg/kg Arjuna bark extract (50% ethanolic) to normal and diabetic rats, reflex bradycardia (a reduction in heart rate in response to high blood pressure, which attempts to normalize blood pressure) was improved in the diabetic rats;^[29] the state of diabetes being known to reduce this reflex.^[30] The alterations in reflex tachycardia (an increase in heart rate in response to low blood pressure) were not improved by Arjuna over 30 days.^[29] The beneficial effects on baroreflexivity has also been noted in isoproterenol (beta-2-adrenergic agonist; like ephedrine) induced cardiac failure,^[31] where Arjuna was able to exert rehabilitative and prophylaxtic protection and reduce both cardiac hypertrophy and fibrosis.

Reflex Bradycardia (Baroreflex) is a mechanism where the heart slows its pulsatile power when blood pressure gets too high, which acts to normalize blood pressure. Arjuna, although the mechanisms are unknown, appears to preserve this reflex in situations where the reflex would be hindered (cardiotoxicity, diabetes). The opposite (reflex tachycardia) may not be influenced

In regards to cardiotoxicity, Arjuna appears to be protective against beta-2-adrenergic agonist induced cardiotoxicity (usually using isoproteronol as a means to induce toxicity) in the range of 100-200mg/kg water or water:ethanolic extracts in rodents;^[31][32] this appears to extend to catecholamine-induced cardiotoxicity as well.^[33]

Other studies in animal models have noted cardioprotection against sodium fluoride-induced oxidative stress,^[34] the chemotherapeutic Doxorubicin,^[35] ischemia-reperfusion,^[36][37] and Carbon tetrafluoride.^[38]

Appears to be protective against catecholamine and stimulant-induced cardiotoxicity after oral ingestion to rodents, and protective against other general stressors such as oxidative stress

Specifically looking at human interventions, in persons with myocardial infarction or ischaemic cardiomyopathy given 500mg of the bark extract after operation and for a subsequent 8 weeks in addition to standard therapy (relative to control, recieving only standard therapy of nitrates and aspirin/beta-blockers) noted an increase in left ventricular ejection fraction (12.32% versus 2.52%) and a reduction in left ventrical mass (20% versus no change) only in the Arjuna group without any observable toxicity.^[39] Higher doses tend to be used, with thrice daily dosing of Arjuna bark water extracts showing benefit in persons with acute myocardial infarction (AMI) by reducing mitral regurgitations (independent risk factor for mortality in persons with AMI^[40]) at 1 month (49%) and 3 months (72%) relative to baseline as assessed by echocardiography,^[41] with improvements in diastolic function (E/A ratio) at 1 month (29%) and 3 months (48%).^[42] 2 weeks of thrice daily dosing of 500mg Arjuna bark water extract alongside standard therapy noted improvements in left ventricle function including ejection fraction, and end diastolic and systolic volume (11 persons with AMI, 1 person with peripartum cardiomyopathy) and benefit to cardiovascular health remained when an open-label follow-up was conducted for 20-28 months.^[43] The study recording mitral regurgitations^[42] made note that a placebo group was given, but the placebo and its relations to active control were not elaborated on.

A trial with a larger sample (58 persons with chronic stable angina and provocable ischemia on a treadmill test) using 500mg Arjuna extract thrice daily against 40mg isosorbide mononitrate (vasodilating drug) as active control noted improved performance on a treadmill test (maximal cardiovascular exercise duration and recovery time) as well as cardiac function (maximal ST depression) where Arjuna was comparable to Isosorbide mononitrate.^[44]

The thrice daily dosing of 500mg Arjuna water bark extract has also been used in one case study on Beta-Thalassemia where a reduction of Lp(a) from 51.8 to 39mg/dL was recorded;^[45] the paper made note of a conference presentation (does not appear to be a publication) where a similar observation was noted.

In regards to human trials on cardiovascular health, a once (but more commonly thrice) daily dosing with even intervals between doses shows benefit to cardiovascular and left ventricle function in persons who have suffered myocardial infarctions, with the benefits appearing to extend to other cardiac conditions (Angina in one trial, Beta-Thalassemia according to a case study). Numerous studies, although many are used alongside standard cardiovascular drug treatment rather than monotherapy and most have small sample sizes and statistical power

In a research model of hypercholesterolemic rabbits the ethanolic extract of Arjuna (100-200mg/kg) over 72 days was able to attenuate the increases in triglycerides, LDL-C, HDL-C, and attenuate the increase in the artherogenic index by 49-80%; when compared to 10mg/kg Atorvastatin, 200mg/kg Arjuna tended to underperform nonsignificantly on all parameters.^[46]

Triglyceride lowering effects have been noted in rats in response to Poloxamer 407, with the ethanolic outperforming the ethyl acetate fraction when 175-350mg/kg is taken alongside P-407.^[47] P-407 is an experimental tool to assess high triglyceride levels by inhibiting LPL activity and preventing cellular uptake of triglycerides.^[48] Another study using chemically induced high triglycerides (triton WR-1339) noted similar effects with only the ethanolic fraction being statistically significant, and was replicated in a diet-induced hypertriglyceridemia model where 250mg/kg of the ethanolic extract over one week.^[49]

One study in smokers using Arjuna extracts at 500mg daily for 2 weeks noted that the impaired flow mediated vasodilation (FMD) seen in smokers is somewhat normalized with Arjuna, but not placebo; the authors attributed this to the antioxidative effects of Arjuna, as they are noted also with Vitamin C.^[50]

The 50% methanolic extract of the bark of Arjuna appears to be able to inhibit alpha-amylase with an IC₅₀ of 302+/-0.55μg/mL, with the bioactives (currently unknown) possibly existing in the water component as the 100% methanolic extract has less inhibitory potential.^[51]

A study using the methanolic leaf extract in streptozotocin-induced diabetic mice noted that 100-200mg/kg bodyweight for 15 days was able to dose-dependently reduce elevated fasting blood glucose, with 100mg/kg attenuating 89% of the increase in blood glucose seen in diabetic control and both 200mg/kg Arjuna as well as the active control of 0.5mg/kg Glibenclamide both normalizing blood glucose.^[52] Similar to the potency observed with glucose, both Arjuna at the higher dose and Glibenclamide drastically reduced serum liver enzymes and cholesterol to near control levels.^[52]

A study assessing the effects of Arjuna (500mg water extract of the bark) with or without Ashwagandha (500mg water extract of the roots) in normal weight young adults over 8 weeks noted that, relative to placebo, maximal oxygen consumption capacity was increased 4.8% and average maximal power output (assessed by Sprinting and measured by a Kinematic Measuring System) increased 3.6% with a decrease of blood pressure from 123.00+/-2.87mmHg to 117.80+/-1.48mmHg (4.3%).^[53] Pairing with Ashwagandha increased the power output to 11.6% with a 10% increase in relative power, and also induced significant improvements in VO2 max and oxygen carrying capacity (both seen with Ashawgandha in isolation).^[53]

At least one study has noted improvements in anaerobic cardiovascular exercise performance (high intensity cardio), and the benefits appear to be somewhat additive with Ashwagandha

An ethanolic extract of Arjuna at 21.42mg/kg and 42.84mg/kg in rats (human equivalents of 3.4 and 6.8mg/kg) who were administered thyroxine (T4, a thyroid hormone at 0.5mg/kg for two weeks) noted that the serum increase in T3 and T4 was attenuated by 42% and 79% by administration of Arjuna; the increase in lipid peroxidation of cardiac and liver tissue by T4 was simulatenously abolished.^[54] Similar effects were noted in euthyroidic rats, but an increase in hepatic lipid peroxidation occurred.^[54] The authors noted that similar effects with the antithyroid drug Propyl thiouracil and hypothesized that Arjuna ethanolic extract has anti-thyroid effects, and due to hyperthyroidism causing cardiac tissue enlargment^[55][56] it is thought this may contribute to the cardioprotective effects observed with Arjuna.

Possible thyroid reducing properties, which need to be replicated with a water soluble extract (and mechanisms explored more). May possibly contribute to cardioprotective effects, although not likely to be the only mechanism (as cardioprotection has been noted in persons with normal thyroid status)

The methanolic extract of Arjuna appears to protect gastric tissue from lipopolysaccharide (LPS) from Heliobactor Pylori, which is known to induce ulcers.^[57] This protective effect has been noted against alcohol (7 day preload), Dexamethasone (10 day preload), and diclofenac sodium (single dose) where 100-200mg/kg of an 80% ethanolic extract conferred absolute protection against ulcer formation from Dexamethasone and alcohol, while 400mg/kg of an acute dose conferred absolute protection against Diclofenac Sodium.^[58] The positive control in this study, Rantidine (35mg/kg Diclofenac, 50mg/kg alcohol, 4mg/kg Dexamethasone) also conferred absolute protection,^[58] and these protective effects against Diclofenac have been replicated with a methanolic extract and thought to be related to the anti-oxidative potential.^[59]

One study noted that Arjuna extracts, especially acetonic extraction, was able to cause death of Staphylococcus aureus bacteria and extended to Escherchia Coli, Acinetobacter sp, Proteus mirabilis, and Candida albicans;^[60] the authors hypothesized that the results suggest that Arjuna may be useful against ear infections (although admittedly preliminary).^[60]

In isolated hepatocytes (HepG2), 5-100mcg/mL of the water extract of Arjuna is able to concentration dependently reduce the biomarkers of oxidation induced by TERT (pro-oxidative agent), with free radicals (ROS) and lipid peroxidation (TBARS) being reduced up to 69% and 62% respectively.^[61] The reduction of antioxidant enzymes by TERT was also significantly attenuated up to 60% (SOD), 82% (Catalase), and Glutathione enzymes (62-65% for peroxidase and reductase; fully preventing any reduction in Glutathione S-transferase).^[61] These antioxidant effects are thought to underlie results achieved with 50mg/kg water extract of Arjuna for 7 days prior to CCL₄ induced hepatotoxicity, where Arjuna significantly prevented the rise in GPT (dose dependent reductions up to 50mg/kg, no added benefit at 100mg/kg), normalized ALP, and increased hepatic levels of antioxidant levels either to control levels (Catalase and Glutathione S-Transferase) or above control (SOD), a potency similar to Vitamin C at the same oral doses.^[62]

250-500mg/kg of a hydroalcoholic extract of Arjuna bark (not an oral study, but the equivalent injected into perfused kidneys) appears to reduce oxidation and concomitantly increase antioxidant enzymes (Catalase and Glutathione).^[1] A preservation of anti-oxidant enzymes in response to CCL₄ is observed to be of similar potency to Vitamin C^[62] and has noted protective effects in the kidneys of Alloxan-induced diabetic rats at oral doses of 250-500mg/kg of the water extract.^[63][64]

Molecules that are found in Arjuna that have been noted to exert protective effects on kidney cells include Casuarinin, a tannin structure, with more potency than the water soluble form of Vitamin E known as Trolox.^[65]

In vitro, Arjuna appears to be able to reduce formation rates of calcium-based kidney stones (calcium oxalate and calcium phosphate tested) with the butanol extract being most effective.^[66]

One study using arsenic-induced testicular damage in rats noted that 4 days pretreatment with isolated Arjunolic acid can prevent oxidative testicular damange and histological changes in response to arsenic.^[67] This study noted that, in vitro, the antioxidant potential of Arjunolic Acid peaked at a concentrated of 0.4mg/mL and this appeared to correlated with an oral intake of 20mg/kg (as 50mg/kg did not confer additional protective benefits) and that the overall protective benefit was near absolute, and sligtly less effective than 100mg/kg Vitamin C.^[67]

One study has noted that Arjunic Acid and arjungenin, as well as their glycosides (Arjunetin and Arjunglucoside II) are able to scavenge free radicals without significantly influence superoxide release from polymorphonuclear immune cells.^[68]

Arjuna, particular Arjunic and Arjunolic acids, possesses anti-oxidative properties directly and in a DPPH assay (in vitro assay of antioxidative potential) has more potency than Vitamin C^[69] or at least comparable at the same concentrations.^[62] This is thought to underlie various protective effects of Arjuna in response to compounds with toxic effects mediated by oxidation such as Adriamycin^[70] cadmium,^[71] and arsenic.^[72] Despite the aforementioned study showing more potency from Arjunolic relative to Vitamin C, studies that compare the two in living systems either note similar protectiv effects^[72] or more from Vitamin C (although this latter study used a much higher dose of Vitamin C relative to Arjunic Acid).^[67]

Arjunic and Arjunolic acid appear to have direct anti-oxidative potential and sequester free radicals; the potency of it appears to be similar to Vitamin C (a few studies suggest more or less, but for the most part is similar)

Arjuna bark extracts have been found to exert antigenotoxic (protective) properties in response to 4-nitroquinoline-N-oxide,^[6] 2-aminofluorene, 4-nitro-o-phenylenediamine,^[73] and Adriamycin,^[70] with the bioactives appearing to be concentrated in the acetone and methanolic extracts.^[6][73]

Compounds in the ethanolic/acetone extracts appear to protect the DNA from damage induced by mutagens; the bioactives are currently unknown, and this does not appear to occur with the water extract (which is used for cardiovascular health)

Oddly, a bacteria that has been noted to produce Taxol (Paclitaxel; chemotherapeutic) has been noted to occur on Arjuna bark;^[74][75] this is different from the bacteria that has been previously found on Taxus brevifolia that herb which has a bacterial strain synthesizing Taxol.

Possesses a novel bacteria on the tree which produces the chemotherapeutic Taxol; practical significance unknown, and Arjuna extracts may not have a Taxol content regardless

In response to incubation with an Ehrlich ascites carcinoma (an undifferentiated carcinoma tumor used in research with high differentiation rates and easy transplantation following injections ^[76]) noted that 9 days of Arjuna leaf methanolic extract was able to reduce tumor size (43-67%; nonsignificantly less effective than 20mg/kg 5-fluorouracil) and survival time was extended 43.9% and 87.9% at 100mg/kg and 200mg/kg, with the higher dose not being significantly different than the active control of 5-fluorouracil at 20mg/kg.^[9] Arjuna leaf extract appeared to have similar effects on white and red blood cell counts as did 5-fluorouracil.

In vitro, the main bioactive Arjunic Acid at 100mcg concentration appears to induce up to 70% cytotoxicity in these cells and has been noted to influence another cancer cell line (Dalton's lymphoma),^[77] with the latter cell line showing up to 90% cytotoxicity with 200mcg/mL of an ethanolic extract of Arjuna Bark^[78] and later being confirmed to reduce DLA tumor cell count in a mouse model by 45% and increase lifespan by 60.42% (50mg/kg) and 60% reduce cell count with a 87.50% increase in lifespan (100mg/kg) following oral ingestion of Arjuna bark extract for 10 days, although the higher dose appears to reduce white blood cell count (50mg/kg not affecting WBCs), 2-10mg/kg were also effective on both parameters, but to a lesser degree.^[78] One other study using 3-4g/kg Arjuna water extract in mice did not specifically measure tumor size, but in a Dalton's Lymphoma cell line the alterations of anti-oxidant enzymes (Catalase, SOD, Glutatione S-Transferase) effectively normalized the reductions, and reduced LDH levels in serum by 71% (relative to tumor control) at the higher dose.^[79]

In a rodent model of DMBA-induced oral carcinogenesis, the water extract of the bark of Arjuna at 500mg/kg appeared to suppress the development of tumors from 100% in control to 30% and reduced average tumor size to 33% of control.^[80] This was associated with less adverse histological changes (keratosis, hyperplasia and dysplasia) and improvments in oxidative biomarkers such as TBARS, and the protective effects were thought to be related to anti-oxidant mechanisms.^[80]

One study noted that a constituent of Arjuna, the hydrolyzable tannin Casuarinin, appears to have anti-proliferative effects in MCF-7 breast cancer cells associated with apoptosis at the G0/G1 phase of cell division.^[26]

^[26]

One study has suggested that Casuarinin may induce apoptosis in human non-small cell lung cancer cells (A549) related to apoptosis at G0/G1 from inducing p21/WAF1 via p53.^[81]

In isolated HepG2 carcinoma cells, 60-100mg/mL of the ethanolic extract of Arjuna Bark is able to induce an apoptotic morphology unto cells in a concentration dependent manner associated with induction of p53.^[82]

In research models of Hepatocellular Carcinoma induced by N-nitrosodiethylamine (one study^[83] duplicated in Medline^[84]) the ethanolic extract of Arjuna bark at 400mg/kg for 28 days was able to normalize TBARS (indicative of lipid peroxidation) in the liver but not serum of animals bearing N-nitrosodiethylamine tumors; this study did not measure size of tumors per se, but suggested this to be a protective effect.^[83]