Pharmacological effects

Rosmarinic acid (RA) is an important caffeoyl ester (phenolic depside) with proven medicinal properties and well characterized physiological functions. Rosmarinic acid is found in substantial sources in the family Lamiaceae (1,2). Salvia lavandulifolia is used as choleretic, antiseptic, astringent, and hypoglycemic drug in Southern Europe and contains high levels of RA (3). Rosmarinic acid-containing Ocimum sanctum (holy basil) is used to reduce fevers and against gastrointestinal disorders in India and has antioxidant properties (2,4). In Mexico, high RA-containing Hyptis verticillata is widely used by Mixtec Indians against gastrointestinal disorders and skin infections (5). In Indonesia and several countries in Southeast Asia, RA-containing Orthosiphon aristatus is known for diuretic properties and is also used against bacterial infections of the urinary system (6). Salvia cavaleriei, a high RA-containing species is used in China for treatment of dysentery, boils, and injuries (7). The antioxidative, antimicrobial, and antiviral effects of Prunella vulgaris indicate its potential as a medicinal herb (8). Rosmarinic acid-containing Origanum vulgare (oregano), Thymus vulgaris (thyme), Ocimum basilicum (sweet basil), and Rosmarinus officinalis (rosemary) are important sources of antioxidants in food preservation (9-11) and for stability and enhancement of anthocyanin and related pigment color in berry based juices (12,13) and have potential health benefits as dietary amylase inhibitor in diabetes management (14).

Many pharmacological effects of RA are known. Rosmarinic acid inhibits several complement dependent inflammatory processes and has potential as a therapeutic agent for control of complement activation diseases (15,16). Rosmarinic acid has been reported to have effects on both the classical C3-convertase and on the cobra venom factor and ovalbumin/antiovalbumin mediated passive cutaneous anaphylaxis (15). Rosmarinic acid also inhibits prostacyclin synthesis induced by complement activation (17,18). Rosmarinic acid is also known to have complement independent effects, such as scavenging of oxygen free radicals and inhibiting elastase and is known to be safe (19). Other actions of RA are antithyrotropic activity in tests with human thyroid membrane preparations, inhibition of complement dependent components of endotoxin shock in rabbits, and the ability to react rapidly to viral coat proteins and so inactivate the virus (15). Rosmarinic acid also inhibits Forskolin induced activation of adenylate cyclase in cultured rat thyroid cells (20) and inhibits external oxidative effects of human polymorphonuclear granulocytes (21).

Recent research has indicated other benefits of RA containing Perilla frutescens on the reduction of lipopolysaccharide (LPS) induced liver injury in D-galactosamine sensitized mice (22). High RA P. frutescens also inhibited lung injury in mice induced by diesel exhaust particles (23) and also had antiallergic effect (24). The antiallergic titer of rosmarinic acid was more effective than tranilast, which is a widely used antiallergic drug (24). Rosmarinic acid also has potential antidepressive-like effect in mice based on a forced swimming test (25). Another interesting study has shown that RA inhibits calcium dependent pathways of T-cell antigen receptor mediated signaling (26). However, investigations so far on pharmacological effects of RA have not clarified the antiinflammatory effects but more evidence suggests RA's ability to block complement activation (27) and to inhibit cyclooxygenase (4).

Research findings on pharmacological potential of RA have substantially increased since 2000. RA synergistically inhibited LDL oxidation in combination with lycopene indicating its potential against atherosclerosis (28). In relation to HIV type 1, RA in addition to being an integrase inhibitor also inhibited reverse transcriptase (29,30). In mice studies, Perilla frutescens rich in RA reduced allergenic reactions using mice ear passive cutaneous anaphylaxis (PCA) reaction (24,31). In another mice model, RA in Perilla extract inhibited allergic inflammation induced by mite allergen (32). In a human clinical study related to allergy reduction, RA enriched Perilla frutescens proved to be an effective intervention for mild seasonal allergic rhino-conjunctivitis (SAR), partly through inhibition of polymorphonuclear leukocytes (PMNL) infiltration into the nostrils, which could contribute to reduction in treatment costs for allergic diseases (33). In mice studies, oral and intraperitoneal administration of RA had antidepressive effects and mechanism was suggested to not involve inhibition of monoamine transporters and monoamine oxidase (25,34). In relation to improvement of kidney related functions, RA has shown suppressive effects on mesangioproliferative glomerulonephritis in rats (35). Inhibitory effect of RA on the proliferation of cultured murine mesangial cells was previously reported (36). In this study, RA inhibited cytokine induced mesangial cell proliferation and suppressed PDGF and c-myc mRNA expression in PDGF mediated mesangial cells (36). Suppressive effects of RA enriched Perilla frutescens on IgA nephropathy in HIGA mice were also observed (37). In other pharmacological studies, RA reduced the defensive freezing behavior of mice exposed to conditioned fear stress (38). In relation to signal transduction, RA inhibited Ca2+ dependent pathways of T-cell antigen receptor mediated signaling by inhibiting the PLC-gamma 1 and Itk activity (26). RA is also known to inhibit TCR induced T cell activation and proliferation in an Lck dependent manner (39-41) and can also influence Lck dependent apoptotic activity (42). In other T cell studies, RA alone and in conjunction with currently used immunosuppressive drugs, inhibited in vitro splenic T-cell proliferation (43). RA enriched herb extract was also shown to have beneficial effects on suppression of collagen induced arthritis (44) and showed significant reduction in tumorigenesis in a murine two stage skin carcinogenesis model (45). Herbal extracts enriched in RA yielded higher inhibition of amylase than purified RA, suggesting RA in synergy with other phenolic compounds may contribute to amylase inhibition for potential modulation of hyperglycemia (14). Recently it was shown that oregano clonal extracts high in RA also have antimicrobial activity against Listeria monocytogenes (46) and Helicobacter pylori (47).

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