Ruta graveolens

Rue

Description

Ruta graveolens L. is a member of Rutaceae family. It is a hardy, evergreen shrub of up to one metre tall, with a characteristic greyish green colour and a sharp unpleasant odour. The leaves are small, oblong, deeply divided, pinnate, glandular dotted. The stems are much ramified. Its flowers are small, yellow and in clusters during spring and summer. They have 4 petals, except for the central flower, which has 5 petals. The fruits are round, brown, small and lobulated. The taste is slightly stinging but is masked by the strong bitter odour. Rue is a native of Southern Europe. In England Rue is one of the oldest garden plants, cultivated for its medicinal use. Having with other herbs, been introduced by the Romans. The leaves are the main part used medicinally.

Constituents

Rue contains coumarins (coumarin, herniarin, gravelliferon, rutaretin), furanocoumarins (bergapten, psoralen, rutamarin), furanoquinoline alkaloids (dictamnine, skimmianine, rutacridone) and the flavonoids rutin and quercetin. Methyl nonyl ketone is a major component of the volatile oil and is used in perfumery and flavourings.1

Pharmacological activities

Anti-inflammatory

A 96% ethanol extract of rue has been shown to inhibit inflammation by 30% in an experimental model of arthritis where rats were administered an oral dose of 500 mg/kg body weight 1 hour prior to production of inflammation by carrageenan injection. The extract also inhibited cotton pellet-induced exudation.2

Inflammation is an essential response, but when uncontrolled it may lead to potentially damaging consequences as seen in several inflammatory diseases. Lipopolysaccharide as an endotoxin, induces septic shock and stimulates the production of inflammatory mediators such as nitric oxide (NO), TNF-α, interleukins, prostanoids and leukotrienes.

NO, prostaglandins and inflammatory cytokines are important pro-inflammatory mediators and are the major targets for the treatment of inflammatory disorders. Free radical NO is produced by nitric oxide synthase (NOS) enzyme as a by-product during conversion of L-arginine to L-citrulline The inducible NOS (iNOS) is induced by stress, pro-inflammatory cytokines like IL-1β, IFN-γ, TNF-α and bacterial lipopolysaccharide. Nitric oxide synthase (NOS) plays a major role in regulating vascular tone, neurotransmission, killing of microorganisms and tumour cells and other homeostatic mechanisms. High levels of NO have been reported in circulatory shock, inflammation and carcinogenesis.

It has been proposed that iNOS mediated, high output production of NO causes cell injury through generation of reactive radicals such as peroxynitrite. It also results in nitrosylation of a number of proteins, some of which are involved in cell signalling. During the inflammatory process, TNF-α and interleukins like IL-1β, IL-12 are produced from macrophages to combat the injury. The uncontrolled feedback inhibition of some of these cytokines results in diseased condition. In some of the inflammatory conditions like rheumatoid arthritis, the natural homeostasis leading to controlled apoptosis/proliferation becomes altered due to imbalance in the cytokine levels. Rutin and quercetin, both constituents of rue, have been shown to decrease nitric oxide along with the reduction in iNOS in vitro and quercetin has also been shown to have the same effect in vivo. The whole plant extract of rue has been observed to inhibit the nitrite level in lipopolysaccharide challenged murine macrophage cells and the inhibition was much more significant than with pure rutin.3

In an endotoxin-induced inflammatory model the methanol (50%) extract of the whole plant as well as a coumarin isolated from rue have been shown to inhibit the expression of inducible nitric oxide synthase (iNOS) in lipopolysaccharide (LPS)-induced macrophage cells. Reduction in cycloxygenase-2 (COX-2) gene expression was also observed. The extract, the fraction and isolated compound was furthermore shown to block the LPS-induced activation of NF-κB through the prevention of inhibitor-kB (IkB) degradation (NF-κB induces the expression of several inflammatory mediators such as iNOS, IL-1β and COX-2 along with many other genes. Inhibitory effect of plant extract was not found for IL-12, IFN-γ, TNF-α or its signalling pathway intermediate genes. However, expression of IL-1β gene was significantly inhibited by the whole plant extract as well as its diethyl ether fraction and the purified compound. IL-1β has been shown to induce chondrocytes to produce several types of reactive oxygen species, including H2O2 and hydroxyl and superoxide radicals.4

Effects on fertility and sexual behaviour

In Iranian traditional medicine, rue was one of the plants used for contraception in both in females and males. Females used it in two forms: immersing a cotton wool in its fresh leaves extract and inserting it into vagina before intercourse or drinking a tea after coitus. In males, a fresh plant extract of leaves was applied on to the penis during intercourse or drunk as a tea before intercourse. In a recent study it was observed that an aqueous extract of rue had an immobilizing effects on human sperm cells.5 This effect was without any impairment in cell viability, mitochondrial function and chromatin structure. After 2 hours, sperm cells were still alive and some extent of motility returned after washing them. So it seems that immobilization of sperm cells is neither to cell death nor ATP depletion or chromatin damage.

Rue has been shown to adversely affect sexual behaviour in rats. An aqueous extract of rue was fed orally to male albino rats at a dose of 500 mg/kg body weight for 60 days. This dose induced a significant decrease in the weight of reproductive organs (p<0.01) when compared to controls. The sperm motility and density in cauda epidydimides and testicular ducts were significantly decreased (p<0.01). A significant decrease (p<0.001) in spermatogenesis activity is observed in somniferous tubules. The testicular cell population of treated rats showed a decrease in number of spermatocytes and spermatids (P<0.001) when compared to controls. Serum hormonal assay indicated a decrease in testosterone and follicular stimulating hormone levels in treated rats. A decrease in number of female rats impregnated by males receiving treatment was observed and demonstrated by a decrease in the implantation sites and viable foetuses number (p<0.01). The ingested extract also suppresses the sexual behaviour in adult male rats expressed by a prolongation of first mount time, increase in intromission latency, decrease in intromissions number, and prolongation of the post-ejaculatory interval. This led to reduction of the ejaculation time and increase of the post ejaculatory intervals. Ingestion of rue markedly abolished aggressive behaviour parameters in adult male treated rats namely, a suppression in lateralization, boxing bouts and ventral presenting postures.6

Rue is also used in many countries as an abortifacient. To determine its effect on pregnancy, the lyophilised hydro-alcoholic extract of its aerial parts was administered orally at a dose of 1000 mg/kg per day to mice between the first and third day of pregnancy (DOP), between the fourth and sixth DOP or between the seventh and ninth DOP. The extract did not cause pre-implantation embryonic loss or re-absorptions however the foetal death rate was increased. Oestrogenic activity was not exhibited by the extract. In another study different preparations of rue were administered orally to female rats (Days 1-10 post coition) and female hamsters (Days 1-6 post coition). The powdered root aerial parts and the aerial parts aqueous extract all showed potential anticonceptive activity in rats. However, none of the above preparations showed oestrogenic activity in hamsters.7 The difference in results between the species may be attributable to antagonism of the pre-implantation oestrogen surge which occurs in rats and not in hamsters, indicating that the anti-oestrogenic effects of rue extracts may not be strong enough for hamsters or humans.8

However, a later study found that aqueous extract of rue resulted in a high proportion of abnormal embryos (p<0.05) and the extract also interfered with pre-implantation development and embryo transport in mice.9

The use of rue as an abortifacient is dangerous. A descriptive retrospective survey was conducted on the calls received by the Montevideo Poison Centre between 1986 and 1999 concerning the ingestion of herbal infusions with abortive intent. A total of 86 cases involving 30 different plant species were identified. The species most frequently involved were rue (Ruta chalepensis/graveolens), cola de quirquincho (Lycopodium saururus), parsley (Petroselinum hortense), and an over-the-counter herbal product named Carachipita. The components of Carachipita are pennyroyal (Mentha pulegium), yerba de la perdiz (Margiricarpus pinnatus), oregano (Origanum vulgare), and guaycuri (Statice brasiliensis). Abortion occurred in 23 cases after the ingestion of parsley, rue, Carachipita, celery, Cedron, francisco alvarez, floripon, espina colorada. Out of the 23 cases, 15 involved only the ingestion of plants, 4 cases used injected drugs (presumably hormones), and in 4 cases there was associated self-inflicted instrumental manipulation. Multiple organ system failure occurred in those patients who had ingested rue (alone or in combination with parsley or fennel), Carachipita, arnica, or bardana. Deaths occurred in one case of Carachipita ingestion and in 4 cases of rue ingestion (2 cases of rue alone, 2 cases of rue with parsley and fennel). Self-inflicted instrumental manipulations were found in 4 of the patients with multiple organ system failure and in one of those who died. The results of this report are not conclusive, but it appears that the ingestion of plants to induce abortion involves the risk of severe morbidity and mortality.10

Acetylcholinesterase inhibitory activity

Alzheimer's disease (AD) is the most common form of dementia among the elderly. In AD patients there are decreased levels of acetylcholine in the brain areas related to memory and learning . Based on the cholinergic hypothesis that memory impairments in patients suffering from AD result from a defect in the cholinergic system, an important approach to treat this disease is to enhance the acetylcholine level in the brain by inhibition of the enzyme acetylcholinesterase (AChE).

Aqueous and methanolic extracts of rue and methanolic extracts of Lavandula angustifolia, Rosmarinus officinalis, Petroselinum crispum, Corydalis spp., and Mentha spicata have been found to have a moderate effect defined as more than 15% inhibition of AChE. All five species contains essential oil with terpenes, a group of compounds reported to have AChE inhibitory activity.

Potassium channel blocking

There are unpublished reports from South America of positive effects on encephalomyelitis disseminata (ED) by long-term treatment with tea made from the rue. Demyelinating diseases lead to the uncovering of axonal potassium channels located beneath the myelin sheath thus rendering conduction of nerve impulse very difficult. Rue has been tested on the excitation process at the nodes of Ranvier of intact myelinated nerve fibres and shown to block the pathologically activated internodal potassium channels which may improve nerve function in ED. This potassium channel blocking effect of rue may also be beneficial in the treatment of multiple sclerosis.11;12

Hypotensive

Rue has been shown to have positive chronotropic and inotropic effects on isolated right atria13 and to prolong the AV nodal refractoriness in isolated rat hearts, suggesting cardiotonic and anti-arrhythmic activities. Both the total plant extract and the alkaloid fraction of rue had a similar trend of action on nodal conduction time and refractoriness. Furthermore, an increased atrioventricular conduction time and functional refractory period was observed. These results suggest that the antiarrhythmic effect of rue may be beneficial in the treatment supra ventricular tachyarrhythmia.14

Antimicrobial

Rue has been shown to have antimicrobial and cytotoxic activities in vitro15 and the furanocoumarins as well as quinoline and quinolone alkaloids have been shown to have antifungal activities.16 The combination of aqueous extracts of rue and Viola odorata (violet leaves) has further been shown to be effective against Trichomonas vaginalis in vitro.17

Apoptosis

Rue has been shown to induce apoptosis (cell death) and could be beneficial in cancer therapy. Furanoacridones and other acridone alkaloids isolated from rue were shown to inhibit the proliferation of three different human cancer cell lines (HeLa, MCF7 and A431).18 An extract of rue was also found to be cytotoxic to Dalton's lymphoma ascites (DLA), Ehrlich ascites carcinoma (EAC) and L929 cells in culture (IC100=16 mg/ml) and also to increase the lifespan of tumour bearing animals. The extract further decreased solid tumours developing from DLA and EAC cells when given simultaneously with elongation of the lifespan of tumour-bearing animals. A homeopathic preparation of <em>Ruta graveolens</em> (200 c) was equally effective. Neither was effective for reducing already developed tumours. The rue extract was found to scavenge hydroxyl radicals and inhibit lipid peroxidation at low concentrations. However, at higher concentrations the extract acted as a pro-oxidant, as inhibition of lipid peroxidation and scavenging of hydroxyl radical was minimal. These data indicate that the pro-oxidant activity of rue may be responsible for the cytocidal action of the extract and its ability to produce tumour reduction.19

Traditional usage

Rue is traditionally used for a very wide range of ailments including menstrual disorders, spasm, loss of appetite, dyspeptic complaints, circulatory disorders, fever, high blood pressure, heart palpitations, inflamed mucosa, toothache, hysteria, arthritis, sprains, injuries and skin diseases.

Ruta species and the Corpus Hippocraticum.

Ruta is a genus of Rutaceae family. It features mainly shrubby plants, native to the Mediterranean region and present in traditional medicine of this region since Antiquity. The three most diffused species Ruta chalepensis L., Ruta graveolens L., and Ruta montana (L.) L., are morphologically poorly differentiated and were probably interchangeably used during Antiquity.

Ruta spp. were mainly employed in medical preparations by Hippocratic physicians as an abortifacient and emmenagogue. In addition to gynaecological conditions Ruta spp. were also recommended as a specific remedy against pulmonary diseases. Ruta spp. leaves and also roots and seeds, were administered for internal use by Hippocratic physicians after having been soaked in wine or mixed with honey or its derivatives.

In his recent synthesis on traditional uses of plants in Italy, the ethnobotanist Paolo Maria Guarrera lists over 100 uses for Ruta angustifolia Pers., Ruta chalepensis L., Ruta corsica DC., and Ruta graveolens L.

All these species are shrubs, whose bluish-green leaves emit a powerful odour and have a bitter taste. Ruta spp. is among the most-used genera in contemporary Italian traditional medicine, economic botany, and folk life. Such possible intensive use is not specific to Italy, but is also documented for other geographical areas of the Mediterranean and other continents. Significantly, the Ruta genus (family Rutaceae) was already abundantly used in the most ancient systematic record of medical practice of the Mediterranean world, the so-called Corpus Hippocraticum. That is, the collection of 62 treatises written between the 5th century BCE and the 2nd century CE that were attributed at a certain point of time to Hippocrates (b. 465 - d. between 375 and 350 BCE).

Ruta spp. was prescribed to treat pulmonary diseases including phthisis, which may correspond at least in part, to modern tuberculosis. It was also used as a gargle against throat angina, and to reduce a swelling of the spleen, which might be one of the symptoms of malaria. Rue is also included among the herbs employed externally to cure wounds.

The majority of therapeutic uses of Ruta spp. are in the area of gynaecology. Ruta spp. were mainly used for the treatment of various ailments of the womb, which are not necessarily well identified. Usteria, for example, which does not correspond by any means to the process described by hysteria in modern neuropsychiatry, was considered to be a move of the uterus within the female body. In so doing, it could disturb respiration, provoking the so-called uterine suffocation, as well as other vital functions. It seems reasonable to consider that the term was a generic one to designate any kind of uterine condition. Ruta spp. was also prescribed for menses disturbance, be it their regulation, amenorrhea or excess. It was administered both as an abortive and to help conception. It was prescribed to treat all the possible disturbances during pregnancy, during the delivery, to expel the placenta, and against puerperal fever. Rue was macerated in, and administered with wine, or mixed with hydromel. In other cases, Ruta spp. was pounded, mixed into wine, and immediately drunk.

In the Hippocratic system there were four humours: blood, phlegm, yellow bile and black bile. As Ruta spp. was credited with hot and dry properties, it could be used either to treat inflammations (heat against heat; principle of similarity) or to reduce any excess of fluids in the body (heat against moisture and cold; principle of contrary).

Ruta spp. was mixed with other herbs, the most frequent of which were coriander, cardamom and turmeric. All these species are not native to the Greek mainland and arrived probably from Near East. It has been suggested that these plants are related to ancient healing cults diffused in Crete. Other plants mixed with Ruta spp. in Hippocratic prescriptions are mint, basil and oregano. These herbs, like Ruta spp. have hot and dry properties according to the system of the four qualities, four elements of the world, and four humours. The combination of these plants with Ruta spp. was probably justified by their common therapeutic action, and their mixture was perhaps aimed at reinforcing such action.

Ruta spp. has been constantly present in the Western material medica from Hippocratic medicine onward. Not only did Dioscorides and Galen mention it in their major works on materia medica On the mixtures and properties of simple medicines, but also late antique manuals of therapeutics such as the Medicines from Vegetables and Fruits by Gargilius Martialis (d. 260 CE) and the Pseudo Apuleius, which was written sometimes in the 4th century CE and circulated widely in the pre-1100 Western world, devoted each a paragraph to the plant. The more typically Western recipe book known as the Lorscher Book of Medicines, used sometimes around 800BC in the Abbey of Lorsch in Carolingian Germany, included it in several prescriptions. In the Arabic world, Ruta spp. is present in the major syntheses on material medica by al Biruni (973-1048 CE), al Ghafiqi (d. ca. 1160 CE) and ibn al Baytar (ca. 1204-1248), as well as in other therapeutic works as those of ibn Butlan (d. 1063 CE [?]) and his contemporary ibn Ridwan (ca 980-1060 CE). In Jordan, rue is used today for its antispasmodic, diuretic, sedative, and analgesic effects and externally for its antirheumatic effect.

With the rediscovery of Greek scientific texts in the Renaissance, the information to be found in Dioscorides' De materia medica was again available and abundantly commented on by contemporary writers including Leonhart Fuchs who wrote the 16th-century herbal the History of Plants (1542). At the turn of the 19th-20th centuries, Georg Dragendorf included it in his manual on herbal medicine for pharmacists.

The plant also attained an increasingly growing symbolic value. Thanks to its numerous little leaves, it was used to sprinkle the Holy Water and to bless people in the Roman rites of the Catholic Church.

Actions

Spasmolytic, antitussive, emmenagogue, uterine stimulant, abortifacient (do not use), antimicrobial.

Indications

  • Pulmonary diseases with cough
  • Worms
  • Rheumatism and other inflammatory conditions
  • Intestinal spastic disorders including gall bladder colic
  • Amenorrhoea where pregnancy has been excluded. To bring on delayed periods (due to shock, stress or other causes) in combination with the uterine tonics.8
  • Other possible uses: Supportive treatment in multiple sclerosis, hypertension and cancer.

Contraindications and cautions

Rue is possibly the plant most used by women with abortive intent, but may potentially cause multiple organ system failure and death.(10) Because of its effects, rue should not be used as an abortifacient. The furanocoumarins and related alkaloids are furthermore mutagenic and should be avoided in pregnancy.1

Rue may produce phototoxic adverse reactions. When psoralens from rue come in contact with the skin that is subsequently exposed to ultraviolet A light, an impressive photo-irritant reaction can occur.20 Acute phyto-photodermatitis with systemic upset in a 2-year old child after contact with rue growing in a garden has been reported.21

Another case reported the unintentional poisoning in a 78-year old woman who developed bradycadia, acute renal failure with hyperkalaemia, and coagulopathy after three days of consuming a decoction made from rue for the treatment of palpitations and heart protection. She was treated with haemodialysis in the emergency department for hyperkalaemia. Her bradycardia and hypotension improved gradually three days later.22

A study of the effects on the liver and kidney of rue extract found that rue does not have harmful on the kidneys and only affects the liver in a minor way. Oral administration of rue ether extract (500 mg/kg body wt) was given to growing rats for 3 weeks. No significant changes were observed in various biochemical and nutritional parameters on administration of the extract apart from a significant elevation of alkaline phosphatase during treatment.23

Herb-Drug Interaction

Rue extract has been shown to inhibit aldehyde oxidase activity (89-96%) at 100 microg/ml in vitro, which was comparable with 10 microM of menadione, a specific potent inhibitor of aldehyde oxidase. Rutin and especially quercertin showed strong inhibition. Aldehyde oxidase is a drug-metabolising enzyme and this suggest rue has the potential to interact with medical drugs.24

Administration and Dosage

Dried herb

0.5- 1 g or by infusion.

Liquid extract (1:1) 30% ethanol

0.5 to 1.0 ml 3 times daily

References

  1. Van Wyk E, Wink M. Medicinal Plants of the World. Arcadia: Briza Publications, 2004.
  2. Ageel AM, Mossa JS, al Yahya MA, al Said MS, Tariq M. Experimental studies on antirheumatic crude drugs used in Saudi traditional medicine. Drugs Exp Clin Res 1989; 15(8):369-372.
  3. Raghav SK, Gupta B, Agrawal C, Goswami K, Das HR. Anti-inflammatory effect of Ruta graveolens L. in murine macrophage cells. J Ethnopharmacol 2006; 104(1-2):234-239.
  4. Raghav SK, Gupta B, Shrivastava A, Das HR. Inhibition of lipopolysaccharide-inducible nitric oxide synthase and IL-1beta through suppression of NF-kappaB activation by 3-(1'-1'-dimethyl-allyl)-6-hydroxy-7-methoxy-coumarin isolated from Ruta graveolens L. Eur J Pharmacol 2007; 560(1):69-80.
  5. Harat ZN, Sadeghi MR, Sadeghipour HR, Kamalinejad M, Eshraghian MR. Immobilization effect of Ruta graveolens L. on human sperm: a new hope for male contraception. J Ethnopharmacol 2008; 115(1):36-41.
  6. Khouri NA, El Akawi Z. Antiandrogenic activity of Ruta graveolens L in male Albino rats with emphasis on sexual and aggressive behavior. Neuro Endocrinol Lett 2005; 26(6):823-829.
  7. Gandhi M, Lal R, Sankaranarayanan A, Sharma PL. Post-coital antifertility action of Ruta graveolens in female rats and hamsters. J Ethnopharmacol 1991; 34(1):49-59.
  8. Trickey R. Women, Hormones and the Menstrual Cycle. Crows Nest: Allen & Unwin, 2003.
  9. Gutierrez-Pajares JL, Zuniga L, Pino J. Ruta graveolens aqueous extract retards mouse preimplantation embryo development. Reprod Toxicol 2003; 17(6):667-672.
  10. Ciganda C, Laborde A. Herbal infusions used for induced abortion. J Toxicol Clin Toxicol 2003; 41(3):235-239.
  11. Bohuslavizki KH, Hansel W, Kneip A, Koppenhofer E, Reimers A. Potassium channel blockers from Ruta--a new approach for the treatment of multiple sclerosis. Gen Physiol Biophys 1992; 11(5):507-512.
  12. Bethge EW, Bohuslavizki KH, Hansel W, Kneip A, Koppenhofer E. Effects of some potassium channel blockers on the ionic currents in myelinated nerve. Gen Physiol Biophys 1991; 10(3):225-244.
  13. Chiu KW, Fung AY. The cardiovascular effects of green beans (Phaseolus aureus), common rue (Ruta graveolens), and kelp (Laminaria japonica) in rats. Gen Pharmacol 1997; 29(5):859-862.
  14. Khori V, Nayebpour M, Semnani S, Golalipour MJ, Marjani A. Prolongation of AV nodal refractoriness by Ruta graveolens in isolated rat hearts. Potential role as an anti-arrhythmic agent. Saudi Med J 2008; 29(3):357-363.
  15. Ivanova A, Mikhova B, Najdenski H, Tsvetkova I, Kostova I. Antimicrobial and cytotoxic activity of Ruta graveolens. Fitoterapia 2005; 76(3-4):344-347.
  16. Oliva A, Meepagala KM, Wedge DE, Harries D, Hale AL, Aliotta G et al. Natural fungicides from Ruta graveolens L. leaves, including a new quinolone alkaloid. J Agric Food Chem 2003; 51(4):890-896.
  17. Al Heali FM, Rahemo Z. The combined effect of two aqueous extracts on the growth of Trichomonas vaginalis, in vitro. Turkiye Parazitol Derg 2006; 30(4):272-274.
  18. Rethy B, Zupko I, Minorics R, Hohmann J, Ocsovszki I, Falkay G. Investigation of cytotoxic activity on human cancer cell lines of arborinine and furanoacridones isolated from Ruta graveolens. Planta Med 2007; 73(1):41-48.
  19. Preethi KC, Kuttan G, Kuttan R. Anti-tumour activity of Ruta graveolens extract. Asian Pac J Cancer Prev 2006; 7(3):439-443.
  20. Eickhorst K, DeLeo V, Csaposs J. Rue the herb: Ruta graveolens--associated phytophototoxicity. Dermatitis 2007; 18(1):52-55.
  21. Furniss D, Adams T. Herb of grace: an unusual cause of phytophotodermatitis mimicking burn injury. J Burn Care Res 2007; 28(5):767-769.
  22. Seak CJ, Lin CC. Ruta Graveolens intoxication. Clin Toxicol (Phila) 2007; 45(2):173-175.
  23. Al Okbi SY, El Sayed EM, Ammar NM, El Sayed NK, Abou-El Kassem LT. Effect of Ruta graveolens L. and Euphorbia peplus L. anti-inflammatory extracts on nutritional status of rats and the safety of their use. Indian J Exp Biol 2002; 40(1):45-48.
  24. Pirouzpanah S, Rashidi MR, Delazar A, Razavieh SV, Hamidi A. Inhibitory effects of Ruta graveolens L. extract on guinea pig liver aldehyde oxidase. Chem Pharm Bull (Tokyo) 2006; 54(1):9-13.