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Indian Journal of Experimental Biology Vol. 37, February 1999, pp. 124-130

Review Article

Pharmacology of (Rosmarinus oificinalis Linn.) and its therapeutic potentials

M R AI-Sereiti', K M Abu-Amerb & P Sena.* 'Oepartment of , Faculty of , AI-Fateh University of Medical Sciences, Tripoli, Libya bOepartment of , Faculty of Science, AI-Fateh Uni versity, Tripoli, Libya

The use of is as old as the mankind. Natural products are cheap and claimed to be sa fe. They are al so suitable raw material for production of new synthetic agents. Rosemary (Rosmarinus officinalis Linn .) is a common househo ld grown in many parts of the world. It is used for flavouring food, a beverage drink, as well as in ; in folk.medicine it is used as an antispasmodic in renal colic and dysmenorrhoea, in relieving respiratory di sorders and to stimulate growth of hair. of rosemary relaxes smooth muscles of trachea and intestine, and has choleretic, hepatoprotective and antitumerogen ic activ ity. The rnost important constituents of rosemary are caffeic acid and its derivatives such as rosmarinic acid . These compounds have antioxidant effect. The phenolic compound, rosmarinic acid, obtains one of its phenolic rings from phenylalanine via caffeic acid and the other from tyrosine via dihydroxyphenyl-Iactic acid. Relatively large-scale production ofrosmarinic acid can be obtain ed from the cell culture of Coleus blumei Benth when supplied exogenously with phenylalanine and tyrosine. Rosmarinic acid is well absorbed from gastrointestinal tract and from the skin . It increases the production of prostaglandin Ez an d reduces the production of leukotriene B4 in human polymorphonuclear leucocytes, and inhibits the complement system. It is concluded that rosemary and its constituents especially caffeic acid derivatives such as rosmarini c acid have a therapeutic potential in treatment or prevention of bronchial asthma, spasmogenic disorders, peptic ulcer, inflammatory di seases, hepatotoxicity, atherosclerosis, ischaemic heart disease, cataract, cancer and poor sperm motility.

Nature is a great chemist. Starting with water, carbon liotany, geographical distribution and f olklore of rosemary dioxide and mineral elements, has shown her Rosemary (Rosmarinus ojJicinalis Linn. Fam. Labiatae) synthetic skill of producing carbohydrates, proteins, fats , is an evergreen branched bushy , attaining a height of vitamins and innumerable secondary metabolites of natural about one metre with upright stems, whitish-blue flowers products 1.2 . The use of plant preparations as food stuff, and dark green which are small with edges turned flavouring agents, dyes, insecticides as well as CNS active, over backward. Underneath these rolled edges are little cardioactive, hypolipidaemic, antimicrobial and antitumour gI'~~ds containing?r,omatic oi ls. It grows wildly along the agents are some examples of immense chemical diversity in north and south coasts of the Mediterranean sea, and al so in 6 8 plants which are as old as mankind. No wonder that we are the sub-Himalayan areas . . It has been cultivated since still looking more and more into the synthetic skill of plants ancient days in England, Germany, France, Denmark and for cheap and potentially unlimited source of a suitable raw other Scandinavian countries, Central America, Venezuela material for the production of new therapeutic agents. With and the Philippines6 Rosemary is one of the ancient cult the development of various analytical methods of high plants, closely associated with love and marriage, birth and precision, and advances in molecular biology and genetic death . In England and Germany it is cons idered as a symbol , it is now possible to isolate compounds in of remembrance and is still used in bridal bouquets and a extremely small quantities, study their chemical structure spring is put in the cradle of a newly born child to protect and therapeutic potentialities and then to alter the molecule against evil influences and forces; it is aiso placed in books to be suitable for production of novel and more selective and among clothes to protect them from moths and to 9 new therapeutic agents. Explosion of research works on produce a pleasant odour . The name of the plant is 4 plants like ), , 8acopa mentioned in some world c1assic6 such as Hamlet and Don ojJicinalis4 and Ocimum .\·anctum5 are some examples that Quixote9 "Rosmarinus" is a Latin word which means "Dew can be mentioned in this regard. Recently, another plant of tile Sea" (Ros =Dew; Marinus=Sea). that has aroused great interest for its therapeutic potentialities is rosemary, a very common household plant. Traditional uses ofrosemary Rosemary plant is cu lti vated for its aromatic oil which is ca ll ed "rosemary oi l" and is obtained by steam distillation *Co rres pondent aut ho r of the fresh leaves and flowering tops of the planto. It is a AL-SEREITI et al.: PHARMACOLOGY OF ROSEMARY 125 colourless or pale yellow liquid having the characteristic phenylalanine for A ring and tyrosine for B ring (Figs , odour of the plant. It is an ingredient for Eau-de-cologne, 1&2). hair tonics, hair lotion, cold cream etc. The leaves are used Important in the biosynthetic pathway of RA for flavouring foods as condiment. Since the ancient days have been identified, purified and attempts to enhance or rosemary has been used in folk medicine for manifold inhibit their activities have been worked out as well. con dIt·· IOns 10- 12 , some 0 f w hIC' h may be enumerated as Prephenate aminotransferase (PAT) from RA-producing follows: cell cultures of Anchusa officinalis has been purified to It has been used as an antispasmodic in renal colic and apparent homogeneity using a combination of high­ dysmenorrhoea and in relieving respiratory disorders. It has performance anion-exchange, chromatofocusing and gel also been used as an , antirheumatic, carminative, filtration chromatographyl7. The purified PAT displays cholagogue, , expectorant, antiepileptic and for high affinity for prephenate and it is not subject to feedback effects on human fertility. Other uses are as a general tonic inhibition from L-Phenylalanine or tyrosine, but its activity in case of excessive physical or intellectual works and in is affected by the RA metabolite, 3,4-dihydroxyphenyl­ heart diseases; and also as an insecticide and herbicide. lactic acid. Externally, it is a rubefacient, and is used to stimulate the Another , tyrosine aminotransferase (TAT) was growth of hair and treatment of eczema of the scalp, boils purified from the cell culture of Anchusa officinalis and and wounds. subsequently has been characterized as TAT -1 , TAT -2 and It is needless to say that such diverse activities of TAT-3, all of them show a pronounced preference for L­ rosemary has generated great interest and its volatile oil, Tyrosine over other aromatic amino acids, and are inhibited I8 plant and some of its isolated constituents have by the tyrosine metabolite, 3,4-dihydroxyphenyl-lactate been subjected for many pharmacological in~estigations. In plants, these phenolic acids form esters with containing OH-group, this link known as depside bond. A Chemistry ofr osemary new analytical method for separation and deternlination of J When the aqueous extract of rosemary was analyzed to aqueous depsides has been developed I. identify the active principles, its chemical composition revealed the presence of many substances whose antioxidant and anti-lipoperoxidant activities have been demonstrated, namely rosmarinic acid (RA), caffeic acid Table I-List of some plants containing caffeic acid (CA) and (CA), chlorogenic acid, carnosolic acid, rosmanol, carnosol rosmarinic acid (RA) 5 and different diterpenes 13.14 , rosmari-diphenoI1 , Plant Antioxidant Reference rosmariquinonel 6 and many other natural antioxidants, 7 I Anchusa ojJicinalis L. RA 17, 18 ursolic acid, glucocolic acid and the rosmaricine . 2 Artemisia campestris CA 19 The rosemary oil contains esters (2-6%) largely as borneol, 3 Artemisia capillaris RA 20 cineoles and several , chiefly a-pinene and 4 Artemisia montana RA 20 6 camphene . 5 Artemisia princeps RA 20 Amongst these compounds, CA and RA became the 6 Calendulla ojJicinalis L. CA 21 focus of attention of researchers as potential therapeutic 7 Carissa spinarum CA 22 agents. They were found to be widely present in many 8 Coleus blumei Benth RA 23 members of the plant kingdom including rosemary. A list of 9 Helianthus annuus L. CA 24 10 ojJicinalis Chaix plants containing CA and RA is given in Table 1. RA 7 II Lithospermum ojJicinalis L. CA 7 12 Lithospermum ruderale CA 25 Chemistry ofrosmarinic acid 13 Lycopus europaeus L. RA 26,27 The bi osynthetic pathways of the phenolic 14 Melissa ojJicinafis CA,RA 26, 27 compounds,CA, dihydroxy-phenyl-Iactic acid (DOPL) and 15 Mentha piperita RA 26, 28 RA 1.28.J2 are depicted in Fig. 1. The chemical structure of 16 Nicotiana tabacuum CA 29 CA, DOPL and RA are given in Fig. 2. 17 Olea europea L. CA 29 Briefly, shikimic acid which is present widely in plants, 18 Origanum vulgare L. RA 26, 27 is a compound of far reaching importance in biosynthesis of 19 Prunella vulgaris L. RA 27 20 Pyrus comunis L. aromatic essential amino acids viz. phenylalanine, tyrosine CA 29 21 Rosmarinus ojJicinalis L. CA, RA 7, 38,27,30 and tryptophan. Synthesis of cinnamic acid arises from 22 aegyptiaca L. RA 7 phenylalanine by enzymatic elimination of ammonia 23 Salvia miltiorrhiza CA, RA 31 (phenylalanine ammonia lyase), followed by aromatic 24 Salvia ojJicinalis L. RA 26, 27 hydroxylation to give CA. RA' (a-O-caffeoyl-3,4- 25 Strychnos innocua Del CA 29 dihydroxyphenyl lactic acid) is an ester of DOPL and CA, 26 Strychnos stuhlmannii Gilg CA 29 Thl'.mus vulgariS L. with different origins for its two C6-CJ units: independently 27 CA 29 126 INDIAN J EXP BIOL, FEBRUARY 1999

Production ofrosmarinic acid by plant cell culture spontaneous contractions of the rabbit . jejunum and Plant cell culture techniques potentially offer the inhibited contractions induced by acetylcholine, histamine 37 possibility for large-scale production of the desired natural and barium chloride • products. RA production has been studied in cell Choleretic and hepatoprotective effects of rosemary­ suspension cultures of Coleus blumei Benth which has been Rosemary has been used empirically as a choleretic and found to accumulate 8-11 % of their dry weight as RA 23. hepatoprotective agent in tradi-tional medicine. These Actively growing tissue converts > 20% of exogenously effects were proved experimentally by us ing the lyophilized supplied phenylalanine and tyrosine to the caffeoyl ester ethanol and aqueous extracts of young sprouts of and this high rate of synthesis coincides with an increase in R. officinalis which have shown a choleretic activity and phenylalanine ammonia-lyase specific activity. offered protection against carbon tetrachloride induced 13 hepatotoxicity in rats . This was evident by a significant Pharmacological actions ofrosemary increase in bile flow and a significant reduction in plasma Effects of rosemary on central nervous system­ liver enzymes when extracts were given as pretreatment Administration of rosemary oil, both by inhalation and by before carbon tetrachloride, but there was no protection oral route, stimulates the CNS, respiratory and locomotor when extracts were given after it. Using an organic activity in mice, suggesting a direct action of one or more hydroperoxide (tert-butyl-hydroperoxide) to induce injury 33 of its constituents . Alcoholic extrac't of R. officinalis in freshly isolated rat hepatocytes, it has been shown that showed antidepressant activity on forced swimming the aqueous extract of the young sprouts of R. officinalis had 34 induced immobility test model in mice . an antilipoperoxidant activity, as it reduced the formation of Effects of rosemary on circulation---Use of rosemary oil malonaldehyde significantly, in a dose dependent manne JC bath is reported to stimulate the skin, improve circulation and significantly decreased the release of lactico·­ and to improve. haemodynam ics in occlusive aI1erial dehydrogenase (LDH) and aspartate aminotransferase 35 diseases . (ASA T), thus confirming the antihepatotoxic action of R. 38 Effects of rosemary on smooth muscle-The volatile oil officir.alis . inhibited the contraction of tracheal smooth muscle induced Antitumorigenic effect of rosemary-The incidence of by acetylcholine and histamine in rabbits and guinea pigs in cancer is associated with mUltiple factors including dietary 2 2 Ca + containing as well as Ca + free solutions, and also and nutritional status. In particular, minor, non-nutrient inhibited the contraction induced by high K+ containing dietary constituents have been reported to be effective 36 so lution . Aqueous extract of rosemary leaves inhibited the inhibitors of experimental carcinogenesis 39-41 _ Some of

Shikimic acid H H~COOH . I. 'd ChonSInlC act HoM H PrephliC acid I Coffeic odd

H~C()()-i HO)..8J OH

p-Coumaric acid Dihydroxyphenyl-loctic acid.

caffeid acid Dihydroxyphenyl-Iactic \ acid (DOPL)

Rosmarinic acid / Fig. I-Biosynthetic pathway of caffeic acid (CA), dihydroxyphenyl-Iactic acid (DOPL) and rosmarinic ac id in some Rosmorinic acid higher plants. Shikimic acid gives the aromatic essential amino ac id s: phenylalanine and tyrosine. Rosmarinic acid comes from Fig. 2~hemical structure of caffeic acid, dihydroxyphenyl-I actic both, CA and DOPL acid and rosmarinic acid AL-SEREITI et al.: PHARMACOLOGY OF ROSEMAR Y 127 these inhibitors have been found to possess a potent Hydroalcoholic extracts of some medicinal plants with hi gh antioxidant activity. extracts of leaves of R. ojJicinalis are amount of hydroxyc innamic derivati ve content (of which widely used as antioxidant in the food and are RA is present in more than 3-6% of the dry weight) were shown to be safe by not producing any acute toxicity in tested and have shown significant antioxidative activiti es, animal tests42 -45 . Extracts of this plant have also been shown by free radical scavenging effect on DPPH. Th e to exhibit an inhibitory activity against KB ce ll s46, an assay anti oxidative acti vity was attributed partly to the hi gh RA 26 27 which is widely used to identify anticancer agents in natural content of these plants . . products. The potentiality of rosemary extract to inhibit In another study with the use of spin trapping methods, chemically-induced mammary tumorigenesis in female rats rosemary extract was reported to have a scavenging effect and to prevent carcinogen-DNA adduct formation in on the ac ti ve oxygen free radical In stimulated 47 mammary epithelial cells was investigated . Dietary polymorphonuclear leucocyte system 5'- . supplement with 1% (w/w) rosemary extract in rats treated (c) Effect of RA on the compleml!nt .\ystelll­ with 7, 12-dimethylbenz (a) anthracene (DMBA) Activation of the complement system can co ntribute to th e significantly decreased the mammary tumorigenesis by 47% inflammatory reaction in a number of ways, such as by and inhibited total in vivo binding of DMBA to mammary increasing the vascu lar permeability and foml ati on of epitheli al ce ll DNA by an average of 42%, suggesting th at oedema; by stimulating chemotaxis of leucocytes: by th e use of rosemary extract and its individual anti oxidant enhancing pl atelet activation and aggregation; by enhancin g consti tuents as chemopreventive agents for tumorigenesis prostaglandin synthes is in macrophages, and by rel eas in g warrant further in vesti gation. lysosoma l enzymes. Several have been shown to Antimycotic activity of rosemary- The problem of modulate the bactericidal ac ti vity of serum complement S.> 5-1. infection with oral candidiasis in immuno-compromised RA was reported to produce an inhibitory ac ti vit y when patients and following the use of drugs such as broad tested in three il1 vivo models in whi ch complement 30 spectrum , corticosteroids and cytotoxic drugs activation pl ays a role Thus, it inhibited pass ive whi ch may not respond to the comm onl y used remedies cutaneous anaphylaxis for egg ova lbumin in the rat in a such as nystatin , has become increasingly manifested dose of 1-100 mg/kg given orall y; it impaired in \'im recentl y. Rosemary oi l remarkably inhibited the growth of acti vat ion of mouse macrophages by heat killed C perl'llill Candida albicans in vitro48 In vivo, it has been reported (ip) in a dose of 10 mg/kg i.m. and in still smal ler dose that when an aqueous emu lsion of rosemary oi l in water (0.3 16-3. 16 mglkg, i.m.) reduced paw oedema in duced by ( I : 10) is appl ied with a cotton swab in the mouth, five times cobra venom factor (CYF) in the rat. The fac t that RA did a day, of patients with different types of cancer and not inhibit t-butyl-hydroperox ide induced paw oedema in pneumonia hav ing candidias is which did not respond to the rat indicates the selj;!ct ivity of RA for the complemcnt treatment with nystatin , the growth of the yeast di sappeared dependent processes30 Experim ents with in "itro completely in 2-4 days49. immunohaemolysis of antibody coated red blood ce lls by guinea pig serum revealed th at ros marini c aci d Pharmacology ofrosemarinic acid causes inhibition of haemolys is by 70% in a concentrati on Pharmacokinetics of RA in rats-RA is absorbed by as low as 5-10 !J.mollL by actin g on th e Crconvert ase of the both oral and parenteral routes of ad ministration with t-half class ical complement pathway. of about 1.8h; half an hour after i.v. administration, it was In another stud y RA was reported to inhibit the detected and measured in brain, heart, liver, lung, muscle, chemiluminescence of porc ine and hum an pol)­ sp leen and bone, with the highest concentration in the lung morphonuclear leucocytes by pre-opsoni zed zymosan or tissue ( 13 times the blood concentration). Upon topical phorbol myri state acetate55 . The killing of E. coli was administration of RA in the form of oi ntment on the hind inhibited by RA at a concentration of 2 mM, but not th at of limb, its bioavailability was about 60% and peak time was Staph aureus. The inhibition of th e ki llin g was due to an 4.5 hr; and it was measurable in blood, sk in , musc le and impaired opsonization, caused by an adverse influence of bone. Alcohol promotes topi cal absorption of RA 50 RA on the complement activati on. Direct effects of RA 0 11 Antiinflammatory action of RA- RA is a naturall y the killing mechanisms of polymorpho-nuclear leucocytes occurring non-steroidal antiinflammatory agent with nove l were not observed. properties which are as follows:

(a) Effects of RA on cell mediators-RA strongly Conclusion and future prospects inhibits the fonnation of 5-hydroxy-6, 8, I I, 14- It is well established that the in creased formation of ecosatetraenoic acid (5 HETE) and leukotriene B4 in human oxygen free radicals may cause ti ssue damage and polymorphonuclear leucocytes, while the fomlation of degeneration and hence may playa role in the path ogenesis prostaglandin E2 is enhanced by CA and several of its of some diseases and acceleration of ageing process . derivatives including RA51. Epidemiological evidence suggests that maintaining hi gh (b) Free radical scavenging activity of RA- intakes of antioxidants such as vitamin E, vitamin C, (3- 128 INDIAN J EXP BIOL, FEBRUARY 1999

carotene and some types of food constituents may help to Table 2-Therapeutic potentials of rosemary plant protect against life-threatening diseases such a" heart 56 disease and cancer . Pharmacological actions Therapeutic potential Oxidative stress is probably an inevitable I. Relaxation of bronchial smooth Bronchial asthma accompaniment of disease with an increase in the activity of muscle the radical-generation enzymes such as xanthine oxidase, 2. Relaxation of intestinal smooth Antispasmodic and activation of phagocytes which may contribute to the muscle disease pathology. This free radical initiation of the propagation of a "chain reaction", can only be halted by an 3. Reduction of leukotrienes and Bronchial asthma antioxidant substance like vitamin E (tocopherol)57, and increase PGE2 production Peptic ulcer will be exaggerated in the deficiency of antioxidants Infl a.mmatory diseases because of the uncontrolled lipid peroxidation, protein 4. Inhibition of lipid peroxidation Hepatotoxicity damage and DNA 'adduction. Atherosclerosis and The accumulated evidence supports that rosemary is one Ischaemic heart disease of the important antioxidants which are commonly used in Inflammatory diseases different nations folk medicine and as a beverage drink. It Asthenozoospermia 38 innibits lipid peroxidation and prevents carcinogen-DNA 47 adduct formation . Increasing utilization of this plant, 5. Inhibition of the complement Inflammatory di seases which has been shown to be safe in toxicity studies in animals and when added as antioxidant to food 4244, can be 6. Prevention of the carcinogen­ Cancer (protection) DNA adduct formation achieved simply by adding it to food for flavouring and by taking it as a beverage drink. The potential benefits of rosemary and its constituents reduced by lowering the low density lipoprotein levels, like RA and the caffeoyl derivatives in the following administration of antioxidants and to increase the production of the beneficial prostaglandins which inhibit diseases, in which oxygen free radicals may play a role 57 (Table 2), remain to be evaluated by clinical trials. platelet aggregation . Rosemary increases production of Rheumatoid arthritis-The rheumatoid joint is a site of prostaglandin E/ ' and has an antioxidant effect, so it may intense oxidative stress, as the large number of phagocytic be beneficial in atherosclerosis. cells, like the polymorphonuclear leukocytes and Coronary artery disease-The consequences of macrophages, at the onset of phagocytosis use membrane coronary artery disease can be minimized by reducing the 5859 NADPH oxidase to generate superoxide anions . The damage resulting from the release of free radicals produced reactive oxygen will cause local damage to prote 'i ns like by xanthine oxidase after the reperfusion (reoxygenation) which may be more pronounced than the damage due to the collagen and denaturation of immunoglobulins which in 64 certain circumstances like, in rheumatoid arthritls both ischaemic anoxia . Antioxidants may help in reducing this 60 effect. might become as autoantigens . Generally in inflammation eiwsanoid production switches from the formation of Hepatotox icity~atty changes and necrosis are due to prostaglandin E , which dampens cellular activation, to the free radical mediated lipid peroxidation and damage to 2 65 synthesis of leukotrienes which are oxidized forms of proteins caused by many noxious agents such as ethanol , 66 arachidonate and this switching promotes aggressive large dose of paracetamol and carbon tetrachloride can be 38 cellular reactions by macrophages, polymorphs and reduced by anti-oxidants . Rosemary may have a beneficial lymphocytes61 . RA has been shown to increase the use in cholestasis as it increases bile fl owlJ. production of prostaglandin E2 and decrease the production Carcinogenesis-Various initiators and promoters of of leukotrienes51and above all it inhibits tht: complement carcinogenesis act via the generation of oxygen free 67 68 C convertase30 resulting in an inhibition of the radicals which cause lipid peroxidation and oxidati ve r 69 inflammatory process. Rosemary as antioxidant may reduce DNA damage . Antioxidants suppress lipid peroxidation the damage caused by the oxygen free radicals to the joint and stop action of promoters67.7o. n Rosemary has been and surrounding tissues. shown to have antioxidant effect with prevention of the 47 carcinogen-DNA adduct formation and so it may be usefu l Atherosclerosis-Atherosclerotic lesions are now in prevention of cancer. thought to be specifically promoted by low density Ulcerative colitis--Excessive accumulation and lipoprotein particles that are oxidized in endothelial celis, activation of phagocytes in th e gut may cause severe 56 macrophages and smooth muscle cells62.63 These particles damage and may be reduced by antioxidants. will be phagocytozed with production of lipid peroxide Cataract-Cataract in old people in volves oxidation and which will cause chemoattraction of more cross-linking of lens proteins. Its development can be monocyte/macrophages and inhibits their motility resulting accelerated by free radicals56 and may be delayed by in the development of atheromatous plaque. This can be antioxidants. AL-SEREITI et al.: PHARMACOLOGY OF ROSEMARY 129

Bronchial asthma-RA increases the production of 18 De-Eknamkul W& Ellis B E, 4rch Biochem Biophys, 257 prostaglandin E2 which is generally bronchodilator while (1987)430. 51 th reduces leukotrienes which are bronchoconstrictors . This 19 AI-Sereiti M R& Abuamer K, In 40 Annual Conference of effect can be enhanced by the inhibition by rosemary of the the Egyptian Society of Pharmacology and Therapeutics, histamine constricting action on the bronchial smooth Cairo, 1996,44. 20 Kimura Y, Okuda H, Okuda T, Hatano T, Agata T& Arichi S, musc1e 36 and by its relaxant effect on the smooth 36 37 Chern Pharm Bull, 33 (1985) 2028. musc1e . The antioxidant effect of rosemary against the 21 Swiatek L & Gora J, Herba Pol, 24 (1978) 187. free radicals, which may have a role in the pathogenesis of 22 Raina M K, Bhatnagar J K &Atal C K, Indian J Pharmacal. 3 bronchial asthma, adds' to its potential preventive use in (1971)76. bronchospasm diseases. 23 Razzaque A & Ellis BE, Planta. 37 (1977) 287. 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