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Ruta graveolens L.

Scientific Name: Ruta graveolens L. Synonyms: Ruta hortensis Mill, Ruta altera Mill, Ruta officinalis Pall. Family: Rutaceae Genus: Ruta Species: graveolens Local name: Rue, Common rue, Herb-of-grace Plant Description: R. graveolens is a small evergreen subshrub or semi-woody perennial 2-3 feet tall and almost as wide. The stems become woody near the base, but remain herbaceous nearer the tips. The 3-5 inches long leaves are dissected pinnately into oblong or spoon shaped segments. They are somewhat fleshy and usually covered with a powdery bloom. The sea green foliage has a strong, pungent, rather unpleasant scent when bruised. The paniculate clusters of small yellow flowers appear in mid-summer, held well above the foliage and often covering most of the plant. Each flower is about 0.5 inch across with four concave notched petals. R.graveolens usually grows in a compact, rounded mound. Chemical Constituents: Common rue contains a mixture of furoquinoline alkaloids in a concentration of approximately 1.5%, the most important of which appear to be arborine, arborinine, and gamma-fagarine. The acridone alkaloids (rutacridone epoxide, hydroxyrutacridone epoxide) are found in greatest concentration in the roots. Other alkaloids include graveoline, graveolinine, kokusaginine, rutacridone, and skimmianine. The flavonoid rutin is also present in the plant and is said to support and strengthen blood vessels, which reduces pressure. A volatile oil is present in a concentration of approximately 0.1%. The oil is 90% methyl-nonylketone with the balance composed of related ketones, esters, and phenols. The plant and its oil are rich in coumarin derivatives, which appear to contribute to the pharmacologic activity of the plant. These furocoumarins include bergapten, psoralen, xanthoxanthin, xanthotoxin, isopimpinellin, and rutamarin. Isolation of such furocoumarins has been performed using an improved extraction technique. Other reports have described isolation of the alkaloid isogravacridonchlorine from rue roots; identification of dihydropyrano- and dihydrofuro-quinolinium alkaloids.

Structures of isolated chemical constituents of Ruta graveolens L.

Rutacridone Rutacridone epoxide

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Graveonline

Gravacridondiol

1-Hydroxy-10-methylacridone Arborinine

Dictamine Kokusaginine

Skimmianine Psoralen

Bergapten Xanthotoxin

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Isopimpinellin Chalepensin

Clausindin Rutamarin

Scopoletin Graveolinine

Graveoline Safrole

β-Sitosterol Parts used: Aerial parts in green seed pod stage. Action of herb: stimulant, anti-spasmodic, emmenagogue, anti-fertility, anti-inflammatory, anti-microbial, abortifacient, aphrodisiac. Medicinal Uses: It is used in hysterical affections, in coughs, croupy affections, colic and flatulence. Rue has been used to treat many ailments, including epilepsy, eye strain, multiple sclerosis, Bell palsy and heart conditions. It is also used as a uterine stimulant to encourage onset

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of menstruation. Rue is indicated for sprains, especially flexor tendon sprains, deposits in joints, especially the wrist, bruised sensations, bruised bones, feeling of weakness and despair. It is beneficial for all injuries of the periosteum and cartilage. Pre-Clinical Studies In isolated rat hearts treated with R. graveolens extract, a concentration-dependent effect increase was seen in atviroventricular-conduction time, Wenckebach cycle length, and effective and functional refractory periods. Rats given a methanolic extract of R. graveolens 20 mg/kg/day for 90 days were found to have lower total cholesterol, low-density lipoprotein levels, and atherogenic indices. Additionally, high-density lipoprotein levels increased in rats given R. graveolens. Oxidative stress and inflammation measures were also reduced. Clinical Studies In a study of 56 patients with colorectal cancer (34 with early stage and 22 with advanced stage), R. chalepensis was found to protect erythrocytes from oxidative stress caused by radicals. Specifically, this effect was noted in patients with early-stage colorectal cancer and was not observed with advanced disease. Preparations and Dosages: Powdered herb, 15 to 30 grains; Fluid extract, 1/2 to 1 drachm;1:1.4 fresh strength liquid extract: 1-4 drops 1-3 times per day. The infused oil is used externally. Side effects & Toxicity: The most common side effect is stomach upset. Rue extracts are mutagenic and furocoumarins have been associated with photosensitization. If ingested, rue oil may result in kidney damage and hepatic degeneration. Large doses can cause violent gastric pain, vomiting, and systemic complications, including death. Because of possible abortifacient effects, the plant should never be ingested by women of childbearing potential. Toxic hepatitis due to Ruta has been reported. Internal overdose will cause gastrointestinal irritation, vomiting, renal irritation, liver degeneration, prostration and death. Externally, excess use of ruta can cause skin irritation resulting in burning, redness and vesiculation. Rue should only be taken with extreme caution. A case report describes multiorgan toxicity in a 78-year-old woman ingesting R. graveolens for cardiovascular protection. After 3 days of use, the patient entered the emergency department with bradycardia, acute renal failure with hyperkalemia necessitating hemodialysis, and coagulopathy. Contraindications: Pregnancy, Lactation, there is a potential for drug interaction with blood thinning agents. Drug interactions: Non-reported Powder microscopy of R. graveolens Microscopic evaluation of R. graveolens powder showed following diagnostic characters of leaves, stem, roots and fruits: epidermis, stomata, trichome, hypodermis, stone cells, fibres, vessels, xylem parenchyma, cork, calcium oxalate crystals and epidermis of pods. See the figures below.

Glandular trichome fibres Anomocytic stomata

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Calcium oxalate crystals stone cells

Figure: Diagnostic microscopic characters of R. graveolens Transverse section examination of R. graveolens The root transverse section had thick walled cork; cortex and hypodermis was distinct; fibres, vessels and medullary rays were lignified. Centre was occupied by pith in root section. In TS of stem, cork cambium was present, initially superficial. Stone cells (oval in shape, abundant in group of 10-15 cells each, with wide lumen, highly lignified) were observed in the cortex. In stem section, centre was occupied by pith, consisting of oval, parenchymatous cells, pericycle was continous and non- lignified. Vessels and fibres were lignified in stem section. In transverse section of leaf, anomocytic stomata were present on both surfaces of leaf. In leaf, epidermis was single layered, thin walled covered with thick, striated cuticle. Trichomes were glandular and had underlying palisade cells. Leaves also had spongy parenchymatous cells. Epidermis of pods shows stomata underlying schizogenous or schizolysogenous cavities with essential oils.

Figure: Transverse section of R. graveolens root

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Figure: Transverse section of R. graveolens stem

Nazish I, Ali M, Mir SR, Parvez N, Yadav S, Hwisa N, Al-Sharif MS, Molvi K. 2010. Application of microscopy in authentication of unani traditional plant Ruta graveolens. An International Journal of Pharmaceutical Sciences. 1(1):

122-127.

Figure: Transverse section of R. graveolens leaf

Nazish I, Ali M, Mir SR, Parvez N, Yadav S, Hwisa N, Al-Sharif MS, Molvi K. 2010. Application of microscopy in authentication of unani traditional plant Ruta graveolens. An International Journal of Pharmaceutical Sciences. 1(1):

122-127. Extractive values of R. graveolens Nazish et al. (2009) determined the extractive values of aerial parts of R. graveolens with different solvents. See the table below.

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Table: Extractive values of R. graveolens

Nazish I, Kaskoos RA, Mir SR, Amin S, Ali M. 2009. Preliminary pharmacognostical standardization of Ruta

graveolens L. aerial parts. Research J Medicinal Plant; 3(2): 41-44. Fluorescence analysis of R. graveolens Nazish et al. (2009) carried out fluorescence analysis of aerial parts of R. graveolens.

Table: Fluorescence analysis of R. graveolens

Nazish I, Kaskoos RA, Mir SR, Amin S, Ali M. 2009. Preliminary pharmacognostical standardization of Ruta

graveolens L. aerial parts. Research J Medicinal Plant; 3(2): 41-44. R. graveolens powder drug reactions with various reagents Nazish et al. (2009) carried out R. graveolens powdered drug analysis. The powdered drug was treated with different chemical reagents.

Table: R. graveolens powdered drug reaction with different chemicals

Nazish I, Kaskoos RA, Mir SR, Amin S, Ali M. 2009. Preliminary pharmacognostical standardization of Ruta

graveolens L. aerial parts. Research J Medicinal Plant; 3(2): 41-44.

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Phytochemical screening of R. graveolens Phytochemical analysis was carried out by Nazish et al. (2009) for the identification of different chemical constituents present in aerial parts of R. graveolens..

Table: Phyto-chemical screening of R. graveolens

Nazish I, Kaskoos RA, Mir SR, Amin S, Ali M. 2009. Preliminary pharmacognostical standardization of Ruta

graveolens L. aerial parts. Research J Medicinal Plant; 3(2): 41-44. Thin-layer chromatography of R. graveolens Thin-layer chromatography of aerial parts of R. graveolens was carried out by Nazish et al. 2009 using toluene: ethyl acetate: diethyl amine: formic acid solvent system (1.3: 0.6: 0.2: 0.5).

Table: Thin-layer chromatography of R. graveolens

Nazish I, Kaskoos RA, Mir SR, Amin S, Ali M. 2009. Preliminary pharmacognostical standardization of Ruta

graveolens L. aerial parts. Research J Medicinal Plant; 3(2): 41-44. High Performance Thin-layer chromatography of R. graveolens High performance thin-layer chromatography of different fractions (ethyl acetate and n-butanol) of R. graveolens was carried out by Naumanet al. (2012).

Figure: HPLC chromatogram of R. graveolens ethyl acetate fraction

Nauman IT, Hamad MN, Hussain SA. 2012. Comparative study of the analgesic activity of two Iraqi medicinal plants, Ruta graveolens and Matricariam chamomilla extracts. J Intercult Ethnopharmacol. 1(2): 79-83.

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Figure: HPLC chromatogram of R. graveolens n-butanol fraction

Nauman IT, Hamad MN, Hussain SA. 2012. Comparative study of the analgesic activity of two Iraqi medicinal plants, Ruta graveolens and Matricariam chamomilla extracts. J Intercult Ethnopharmacol. 1(2): 79-83.

Analysis of R. graveolens essential oils by GC-MS Soleimani et al. (2009) obtained essential oils from aerial parts of R. graveolens and carried out their analysis by GC-MS. See the table and figure below.

Table: Percentage composition of the essential oils of aerial parts of R.graveolens

Soleimani M, Azar PA, Tehranil MS, Rustaiyan A. 2009. Volatile composition of Ruta graveolens L. of north of

Iran. World Applied Sciences Journal. 7(1): 124-126.

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Figure: GC/MS chromatogram of essential oils extracted from R. graveolens

Soleimani M, Azar PA, Tehranil MS, Rustaiyan A. 2009.Volatile composition of Ruta graveolens L. of north of Iran. World Applied Sciences Journal. 7(1): 124-126.

Anti-platelet activity of R. graveolens Wu et al. (2003) explored the anti-platelet activity of the nineteen isolated compounds from methanolic extract of root and aerial parts of R. graveolens. Amongst the nineteen isolated compounds, six compounds (dictamine, skimmianine, psoralen, chalepensin, clausindin, and graveolinine) exhibited potent anti-platelet activity against platelet aggregation caused by arachidonic acid and collagen. Cytotoxic activity of R. graveolens Wu et al. (2003) studied the cytotoxic effects of the nineteen isolated compounds from methanolic extract of root and aerial parts of R. graveolens. Out of nineteen isolated compounds, five (Arborinine, dictamine, isopimpinellin, clausindin, and graveoline) revealed significant cytotoxic activityagainst KB, Hela, DLD, NCI and Hepa tumor cell lines. Anti-oxidant activity of R. graveolens Sailani and Moeini (2007) explored the dose-dependent anti-oxidant activity of 70% methanolic extract of R. graveolens on Guinea pig liver aldehyde oxidase enzyme and revealed 89-96% inhibition.

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Anti-inflammatory activity of R. graveolens Ratheesh& Helen (2007) and Ratheesh & Shyni (2009) found maximum inhibition of carrageenan induced rat paw edema (90.0%) on administration of methanolic extract of R. graveolens (20mg/kg) and ethanolic R. graveolens extract (50mg/kg) respectively. Anti-arrhythmic activity of R. graveolens Khori et al. (2008) explored the effect of alkaloidal extract of Ruta graveolenson isolated rat hearts and found a potential antiarrhythmic effect. Extracts of Ruta graveolens significantly prolongs refractory periods and nodal conduction time in a rate dependent manner. The effects of the extract appeared on both the slow and fast pathways of the node. Anti-fertility activity of R. graveolens The uterotonic activity of methanol extract fractions (ethyl acetate, n-butanol and aqueous fraction) as well as the isolated major compounds of R. graveolens were tested in the isolated mouse uterus in vitro. The n-butanol-soluble fraction of R. graveolens was found to demonstrate the most potent uterotonic activity in a dose-dependent manner, also the major isolated compound rutin revealed the occurrence of an uterotonic response, which was maximum at a concentration level of 0.25 mg/mL, accounting for 68.7% of that exhibited by the chosen concentration of oxytocin. Analgesic activity of R. graveolens Naumanet al. (2012) carried out analgesic activity of R. graveolens ethyl acetate extract and observed significant analgesic activity. Vasodilatory activity of R. graveolens Fernández et al. (2013) evaluated the effect of R. graveolens extract against rat aortas rings with and without endothelium.The vasodilatation activity is affected in subtoxic concentration and partially endothelium-depend without permeability effect in the membrane and deterioration of the cells viability suggesting a complex effect of R. graveolens in the regulation of vascular tone.

Figure: (a) Vasodilatory activity of the R. graveolens extract in concentrations of 1, 5, 10, 50, 100 and 1000µg/ml in conditions of with and without endothelium with aortas of rats Sprague Dawley and incubated in isolated organ bath; (b) Effect doses-depend, sigmoidal curve of treatment, DE50 19µg/ml for the dilatation of aortas. Results shown are mean ± SEM (n = 8), significant difference (**P<0.01), (***P <0.001). Fernandez IJ, Gomez PN, Parodi J, Mejia FR, Salazar RS. 2013. Chilean crude extract of Ruta graveolens generates vasodilatation in rat aorta at cellular subtoxic concentrations. Advaces in Bioscience and Biotechnology. 4: 29-36.

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Effect of R. graveolens on spontaneous motor activity in rats Saad et al. (2015) explored that alcoholic extract of R. graveolens decreased the number of squares visited and rearing by increasing the concentration of R. graveolens. See the table below.

Table: Effect of R. graveolens on spontaneous motor activity in rats

Saad SEA, Aburawi SM, Fong I, Abdalla SO, Elouzi AA, Shubar HM, Al-gadamsy MT. 2015. Studying the effects

of Ruta graveolens on spontaneous motor activity, skeletal muscle tone and strychnine induced convulsions in albino mice and rats. International J Research in Pharmacology & Pharmacotherapeutics. 4(1): 53-58.

Skeletal muscle relaxation activity of R. graveolens Saad et al. (2015) studied the effect R. graveolens on smooth muscle tone in rats in both the pull-up and rod hanging tests. R. graveolens extract exhibited more significant results in rod hanging test. See the table below.

Table: Effect of R. graveolens on skeletal muscle tone in rats

Saad SEA, Aburawi SM, Fong I, Abdalla SO, Elouzi AA, Shubar HM, Al-gadamsy MT. 2015. Studying the effects

of Ruta graveolens on spontaneous motor activity, skeletal muscle tone and strychnine induced convulsions in albino mice and rats. International JResearch in Pharmacology & Pharmacotherapeutics. 4(1): 53-58.

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R. graveolens effectiveness against strychnine induced convulsions The effectiveness of R. graveolens extract was observed by Saad et al. (2015) on strychnine-induced convulsions in mice. Alcoholic extract reduced the number of deaths in mice from 100% to 33%. R. graveolens also inhibited the strychnine induced myoclonic convulsions in mice. See the table below.

Table: Effect of R. graveolens on strychnine induced convulsions in mice

Saad SEA, Aburawi SM, Fong I, Abdalla SO, Elouzi AA, Shubar HM, Al-gadamsy MT. 2015. Studying the effects

of Ruta graveolens on spontaneous motor activity, skeletal muscle tone and strychnine induced convulsions in albino mice and rats. International Research in Pharmacology & Pharmacotherapeutics. 4(1): 53-58.

Effect of R. graveolens extract on rat tracheal ring Aguilaet al. (2015) studied the relaxant effect of hydroalcoholic extract of R. graveolens on rat tracheal rings. Anti-hyperglycaemic and anti-hyperlipidemic activities of R. graveolens Ahmed et al. (2010) studied the anti-hyperglycaemic and anti-hyperlipidemic activities of R. graveolens in diabetic rat model and observed significant activities.

Figure: Oral glucose tolerance curves of normal, diabetic control and diabetic rats treated with R. graveolens and rutin. Ahmed OM, Moneim AA, Yazid IA, Mahmoud AM. 2010. Antihyperglycemic, anti-hyperlipidemic and antioxidant effects and the probable mechanisms of action of Ruta graveolens infusion and rutin in nicotinamide streptozotocin-

induced diabetic rats. Diabetologia Croatica; 39(1):15-35.

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