Antioxidant activities of carnosol

and carnosic acid in food and

biological model systems - A review
Part 1
SUBHASHINEE S. K. WIJERATNE*, SUSAN L. CUPPETT
*Corresponding author

Antioxidants
Department of Food Science and Technology
University of Nebraska-Lincoln, Lincoln, Nebraska, 68583-0919, USA

OXIDATIVE STRESS
Oxidative stress in a biological system describes the
disturbance in the cellular prooxidant-antioxidant balance in
the favour of the former (1). It is imposed on a cellular system
when the generation of ROS exceeds the system's ability to
neutralize and/or eliminate them (2). An imbalance of
production and removal of ROS can result from a lack of
antioxidant protection, overabundance of ROS from the
environment and/or a failure to repair oxidative damage. If not
regulated properly, excess ROS can damage cellular
components and inhibit normal function, which can lead to the
pathogenesis of several human diseases (3).
Living cells are continuously involved in redox pathways that
lead to the production of ROS, such as free radicals and other
non-radical reactive oxygen derivatives such as peroxides. A
free radical is a chemical species capable of independent
existence that possesses one or more unpaired electrons (2).
Free radicals are produced from endogenous sources as by-
within each cell, can initiate the growth of abnormal cells,
which is the first step in cancer development, and (iv)
damages to lysosomes: lysosomes contain cellular
degenerative enzymes, which leak out when the cell
membrane is damaged. The enzymes start digesting the cell
itself, causing a chain reaction of destruction that eventually,
will lower the immune system resistance (8, 9). Such damages
to various molecules and cells have been implicated in several
diseases, including cancer, arthritis, atherosclerosis, ischemic
damage following stroke, premature aging, and a variety of
neurodegenerative disorders (2, 6, 10-12). Some of the major
ROS found in biological systems are listed in Table 1.
.
Superoxide −
radical (O2 ) is
produced by the
activity of
oxidases during
oxidative 7
metabolism in

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products of electron transport, oxygen-utilizing systems, and living cells (13).
other processes involved in normal aerobic metabolism, lipid When an
peroxidation, viral, fungal and bacterial infections, and electron is
detoxification reactions involving the liver cytochrome P-450 transferred to
enzyme system (4, 5). Exogenous sources include cigarette oxygen during
smoke, environmental pollutants, such as emission from reduction of
automobiles and industries (ozone and nitrous oxide), oxygen (O2) to Table 1. Free radicals and non-radical


.
November/December 2006
asbestos, consumption of alcohol in excess, and exposure to water−
(H2O), products found in biological systems
ionizing radiation (from industry, sun exposure, cosmic rays, O2 is
and medical X-rays) (6, 7). generated as shown in Figure 1. This mechanism protects
Four types of damage are initiated by ROS: (i) damage to fat animals by killing bacteria in activated phagocytes (6).
compounds: free radicals mainly target polyunsaturated fatty Superoxide radical formation can also occur by the transfer of
acids and cholesterol located in the membranes surrounding an electron from a transition metal ion, such as ferrous (Fe2+),
the cells, thus a damaged membrane loses its ability to to O2 (13). Superoxide is less reactive compared to many of
transport oxygen, nutrients, and water to the cells; (ii) damage the free radicals listed in Table 1. It is not particularly reactive


to protein molecules: results in defective cell membranes and with lipids, carbohydrates and nucleic acids but exhibits some
Anno 17 - No. 6

loss of enzyme activities; (iii) damage to nucleic acids: activity against proteins (14), especially proteins that contain
alterations in nucleic acids, which comprise the genetic code heme-moieties (15) or iron-sulfur clusters (16). The main

ABSTRACT .
destruction by superoxide radical is due to the formation of
hydroxyl radicals (HO ) (9).
Oxidative stress occurs in biological systems due to an increase in
oxidant generation, a decrease in antioxidant activity, and/or failure to
repair oxidative damage. Reactive oxygen species and other free
radicals present in the environment and that are derived from dietary
sources are oxidative stress inducers. Dietary antioxidants play an
important role in restoring the oxidant-antioxidant balance in biological
systems when the existing cellular antioxidant defence mechanisms
fail to combat increased levels of oxidizing agents. Antioxidants,
carnosol and carnosic acid, derived from rosemary (Rosemarinus
officinalis L.) leaf extracts, have shown to exert strong antioxidant
activities against reactive oxygen species and free radical attacks in
food as well as biological model systems.
Figure 1. Role of oxygen in producing reactive oxygen species
 Hydrogen peroxide (H2O2), present in low concentrations in
aerobic cells as a metabolite, is less reactive because it is not
a free radical. It is generated during superoxide dismutase-
catalyzed dismutation reactions (17), oxidation of D-amino
acids by D-amino acid oxidases, and action of xanthine
oxidase upon xanthine and hypoxanthine to form uric acid
(18). Hydrogen peroxide is also converted to hypochlorous
acid by myeloperoxidase in neutrophils. Hypochlorous acid is
a strong oxidant that acts as a bactericidal agent in phagocytic
cells. However, the biologically significant reaction of H2O2 is its
.
spontaneous conversion, catalyzed by Fe2+ (Fenton reaction)
(Reaction I), to the highly reactive HO (6).
H2O2 + Fe2+ −−−−−
.
> HO + OH- + Fe3+
Antioxidants
[I]
Hydroxyl radical can also be generated by exposing water to
high-energy ionizing radiation (6). This radical reacts
instantaneously with any biological molecule from which it
can abstract a hydrogen atom, including DNA, proteins,
.
lipids, and carbohydrates (9). Figure 2 depicts the effects of
HO in a biological system.
8 chalcones), diterpenes, cinnamic acid
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Figure 2. Effects of hydroxyl radical on biological molecules
[Adapted from Acworth et al. (9)]
Hydroperoxyl is another highly reactive radical derived from
O2. Production of this radical is favoured under acidic

November/December 2006
conditions, and its lipophilicity enables it to move across cell
membranes easily to initiate peroxidation of polyunsaturated
.
fatty acids in cell membranes (9).
.
Nitric oxide (NO ) is a weak oxidizing agent, whereas,
nitrogen dioxide (NO2 ) is a powerful oxidizing agent found
in polluted air, cigarette smoke, and smoke of burning
organic material (6). Oxides of nitrogen are important agents
.
in defending living cells against attack by foreign organisms.

.
Anno 17 - No. 6
However, excess production of NO during infections can
lead to formation of NO2 , which abstracts hydrogen atoms
from cell membrane lipids initiating lipid peroxidation (18).
Lipid peroxyl radicals and hydroperoxides, produced during
food lipid oxidation, are implicated in many intestinal
pathological conditions, such as inflammation and cancer.
Studies have shown that existing cellular antioxidant
defence mechanisms are incapable of neutralizing the
damaging effects of dietary lipid hydroperoxides (19), which
highlights the importance of dietary antioxidants in
combating excessive oxidants and free radicals.
ANTIOXIDANTS
An antioxidant is defined as a substance that when present
at low concentrations compared to those of an oxidizable
substrate, significantly delays or inhibits oxidation of that
substrate (6). Porter (20) considered an antioxidant as any
acidic compound (including phenols) usable in foods which
can readily donate an electron or a hydrogen atom to a
peroxyl or alcoxyl radical to terminate lipid peroxidation
chain reaction or to regenerate a phenolic compound, or
which can effectively chelate a prooxidant transition metal.
Biological systems are protected against oxidative damage
by their built-in antioxidant defence system and by dietary
antioxidants. The endogenous antioxidant defence system is
composed of two components: antioxidant enzymes that will
be discussed in the following sections, and low molecular
weight antioxidants that include vitamins A and E, ascorbate,
glutathione, ubiquinone and thioredoxin, and proteins such
as transferrin, ferritin, ceruloplasmin, hemopexin,
hepatoglobin and albumin that are capable of chelating
metal ions (9). These substances are the body's natural
defence against ROS generated by endogenous and
external environmental factors (21, 22).
Naturally occurring antioxidants are primarily plant phenolic
compounds that may be present in any plant part. There are
also synthetically derived antioxidants permitted for food use
such as butylated hydroxyanisole (BHA),
butylated hydroxytoluene (BHT), propyl
gallate (PG), dodecyl gallate and tertiary
butyl hydroquinone (TBHQ) (23). The
growing interest in replacing synthetic
antioxidants by natural ones has brought
about research on plant parts, both edible
and non-edible, for identifying new
antioxidants. Examples of compounds
isolated from plant parts that possess
antioxidant activity include tocopherols,
carotenoids, flavonoid compounds (flavones,
flavonols, isoflavones, catechins, flavonones,
derivatives (caffeic acid, ferulic, chlorogenic
acid), and coumarins (24, 25). To be used in
a food system an antioxidant must (i) be
safe; (ii) not impart any colour, odour or
flavour; (iii) be effective at low
concentrations; (iv) survive processing
conditions; (v) be stable in finished products; (vi) be fat
soluble; and (vii) be readily available at a low cost (24).
ROSEMARY ANTIOXIDANTS
Many herbs and spices have been found to exhibit
antioxidant activity in food systems (26). Commercially
available rosemary extracts that are widely used in the food
industry exhibit potent antioxidant activity (27). Among the
many flavones, diterpenes, triterpenes, and steroids isolated
from rosemary extracts, the main two compounds that
account for 90 percent of its antioxidant activity are carnosic
acid and carnosol (26). Several other diterpenes such as
rosmanol, epirosmanol, isorosmanol (28), rosmaridiphenol
(29), and rosmariquinone (30, 31) have also been reported
to possess antioxidative activity. Carnosic acid is first
converted to carnosol, and then to rosmanol, epirosmanol or
7-methyl-epirosmanol when subjected to heat or oxygen in
the presence of light (32, 33). Therefore, the presence of
high amounts of carnosol relative to carnosic acid is
expected in commercial rosemary extracts, as heating is
involved in the extraction process (24).
Antioxidant activity of rosemary extracts and compounds
isolated from these extracts has been extensively tested in
food model systems. Rosemary extracts have effectively
inhibited lipid oxidation as measured by conjugated diene
hydroperoxide formation in bulk vegetable and fish oil model
systems but were inactive in oil-in-water emulsion systems
(34). The reason for this response has been described by
the 'polar paradox' phenomenon which indicates that polar
antioxidants are more effective in non-polar lipid systems,
whereas non-polar antioxidants are more active in lipid
emulsions (35). Hydrophilic antioxidants offer more
protection in bulk oil systems by orienting in the air-oil
interface, whereas in oil-in-water emulsions partitioning into
the water phase dilutes the effectiveness of the polar
antioxidants in inhibiting lipid oxidation (34). Lipophilic
antioxidants are distributed more in the oil phase and orient
at the oil-water interfaces, and therefore are more effective
in emulsions compared to hydrophilic antioxidants (36).
Similar effects were observed when carnosic acid and
carnosol isolated from rosemary extracts were tested in oil
model systems. Carnosic acid is more hydrophilic than
carnosol due to its free carboxylic acid group (37); however,
carnosic acid has a greater affinity towards the oil phase
than to the water phase in water-oil mixtures that did not
contain an emulsifier (36). Carnosic acid was relatively more
active in inhibiting lipid oxidation in bulk oil, while less-polar
carnosol performed better in oil-water emulsions (38). Also
when antioxidative capacities were evaluated in lard at 100
°C, carnosic acid was more capable of preventing lipid
oxidation than carnosol (39). The antioxidant activity of
rosemary compounds is due to their ability to donate
hydrogen and neutralize free radicals (40, 41). The
antioxidant mechanism proposed by Masuda et al. (40)
shows that carnosic acid undergoes oxidative coupling
reactions with peroxyl radical at 12- and 14- carbon atoms
followed by degradation reactions to form o-quinone and p-
hydroxyl quinone derivatives.
The antioxidant activity is determined not only by their
hydrogen donating ability but also by their relative oxidative
stability in different phases as observed in several food
model systems. In bulk oil and oil emulsions, carnosic acid
was less stable compared to carnosol, but the oxidative
products of carnosic acid still possessed similar or increased
antioxidant activities in these systems (36). In a given
system, carnosic acid and carnosol have also shown
significant differences in their antioxidative activities with
changing pH. In corn oil emulsions, both carnosol and
carnosic acid were highly active at pH 4 and 5, whereas no
activity against lipid hydroperoxide and hexanal formation,
which are by-products of lipid oxidation, was exhibited at pH
7 (34). These results suggest that carnosol and carnosic
acid are more stable in low pH conditions.
Apart from antioxidant activities rosemary compounds also
possess many other biological activities. They have
exhibited capabilities in inhibiting experimental
carcinogenesis in animal models (42-44). Carnosic acid and
carnosol inhibit lipid absorption in the gastrointestinal tract
by inhibiting lipase, an enzyme that breaks down dietary fats
(45), indicating the potential use of these compounds in
weight loss management. Studies have shown that carnosic
acid stimulates the synthesis of nerve growth factor (NGF),
which is an agent that can help reverse the nerve cell
damage and death caused by Alzheimer's disease (46).
We recently investigated the effects of carnosol and
carnosic acid against lipid hydroperoxide induced oxidative
stress in Caco-2 cells. Our studies showed that incubating
Caco-2 cells for 24 h with carnosic acid and carnosol
significantly reduced lipid hydroperoxide mediated cell
toxicity. We also observed that carnosic acid was more
effective compared to carnosol in inhibiting lipid
Antioxidants
hydroperoxide induced lipid peroxidation and DNA damage
in the Caco-2 cells. The effects of carnosol and carnosic
acid on antioxidant enzymes, catalase, superoxide
dismutase and glutathione peroxidase were dependent upon
the compound and their concentrations at supplementation.
Our results also showed that carnosic acid compared to
carnosic acid was able to increase glutathione peroxidase
activity in Caco-2 cells.
REFERENCES AND NOTES
1. Sies, H. and Cadenas, E. Oxidative stress: damage to intact
cells and organs. Philos. Trans. R. Soc. Lond. B. Biol. Sci.
1985, 311, 617-631.
2. Halliwell, B. Free radicals and antioxidants: A personal view.
Nutr. Rev. 1994, 52, 253-265.
3. Salem, H., and Baskin, S. I. Toxicity of oxygen and ozone. In
Oxidants, Antioxidants, and Free Radicals. Eds., Baskin,
S.I., Salem, H., Taylor and Francis, Washington, DC. 1997,
pp 227-235.
4. Ames, B. N., and Shigenaga, M. K. Oxidants are a major
contributor to cancer and aging. In DNA and Free Radicals;
Halliwell, B., Aruoma, O.I., Eds.; Ellis Horwood ltd: West 9
AgroFOOD industry hi-tech
Sussex, England, 1993, pp 1-15.
5. Cederbaum, A. I. Oxygen radical generation by microsomes:
role of iron and implications for alcohol metabolism and
toxicity. Free Rad. Biol. Med. 1989, 7, 559-67.
6 Halliwell, B. and Gutteridge, J. M. C. Free radicals in
Biology and Medicine; Oxford University Press: Oxford, New
York, NY, 1999.
7 Pryor, W. A. Biological effects of cigarette smoke, wood
smoke, and the smoke from plastics: the use of electron

spin resonance. Free Rad. Biol Med. 1992, 13, 659-676.
November/December 2006
8. Yoshikawa, T., Naito, Y., and Kondo, M. Free radicals and
diseases. In Food and free radicals. Eds., Hiramatsu, M.,
Yoshukawa, T., Inoue, M. Plenum Press, New York, NY.
1997, pp 11-19.
9. Acworth, I. N., McCabe, D. R., and Maher, T. J. The analysis
of the free radicals, their reaction products, and
antioxidants. In Oxidants, Antioxidants, and Free Radicals.
Eds., Baskin, S.I., and Salem, H., Taylor and Francis,
Washington, DC. 1997, pp 23-77.

10. Beal, M. F. Oxidatively modified proteins in aging and
Anno 17 - No. 6
disease. Free Rad. Biol. Med. 2002, 32, 797-803.
11. Ames, B. N., Shigenaga, M. K., and Hagen, T. M. Oxidants,
antioxidants, and the degenerative diseases of aging. Proc.
Natl. Acad. Sci. 1993, 9, 7915-7922.
12. Kehrer, J. P. Free radicals as mediators of tissue injury. Crit.
Rev. Toxicol. 1993, 23, 21-48.
13. Yuan, Y. V. and Kitts, D. D. Endogenous antioxidants: Role
of antioxidant enzymes in biological systems. In Natural
antioxidants chemistry, health effects and applications. Ed.,
Shahidi, F., AOCS Press Champagne, IL. 1997, pp 258-270.
14. Davies, K. J. A. Oxidative stress: the paradox of aerobic life.
In Free radicals and Oxidative Stress: Environment, Drugs
and Food Additives. Biochemical Society Symposium 61.
Eds. Rice-Evans, C., Halliwell, B., and Lunt, G. G. Portland
Press, Portland Place, London. 1994, pp. 1-31.
15. Thillet, J., and Michelson, A. M. Oxidation and cross-linking
of human hemoglobins by activated oxygen species. Free
Radic. Res. Commun. 1985, 1, 89-100.
16. Agbas, A., Chen, X., Hong, O., Kumar, K. N, and Michaelis,
E. K. Superoxide modification and inactivation of a neuronal
receptor-like complex. Free Rad. Biol. Med. 2002, 15, 512-
524.
 17. Kanner, J. Mechanism of nonenzymic lipid oxidation in
muscle foods. In Lipid Oxidation in Food. Ed. St. Angelo, A.
J. American Chemical Society: Washington, DC, 1992, 55-
73.
18. Gutteridge, J. M. C. and Halliwell, B. Antioxidants in
Nutrition, Health and Disease. Oxford University Press Inc.,
New York. 1994.
19. Wijeratne, S.S.K., and Cuppett, S.L. (2006). Lipid
hydroperoxide induced oxidative stress damage and
antioxidant enzyme response in Caco-2 human colon cells.
Journal of Agricultural and Food Chemistry, 2006, 54, 4476-
4481.
20. Porter, W. L. Paradoxical behavior of antioxidants in food
and biological systems. In Antioxidants Chemical,
Physiological, Nutritional and Toxicological Aspects. Ed.,
Williams, G.M. Princeton Scientific Publishing Co. Inc.
Antioxidants
Princeton, NJ. 1993, pp 93-122.
21. Porta, E.A. Role of oxidative damage in aging process. In
Cellular Antioxidant Defense Mechanisms Volume III. Ed.,
Chow, C. K. CRC Press, Boca Raton, FL. 2000, pp 2-52.
22. Radi, R. Biological antioxidant defenses. In Antioxidants
Chemical, Physiological, Nutritional and Toxicological
Aspects. Ed., Williams, G. M. Princeton Scientific
Publishing Co. Inc. Princeton, NJ. 1993, pp 53-62.
23. Papas, A. M. Oil soluble antioxidants in foods. In
Antioxidants Chemical, Physiological, Nutritional and
Toxicological Aspects. Ed., Williams, G.M. Princeton
Scientific Publishing Co. Inc. Princeton, NJ. 1993, pp 123-
149.
24. Cuppett, S. L., Schnepf, M., and Hall III, C. Natural
antioxidants: are they a reality? In Natural antioxidants,
Chemistry, Health effects, and Applications. Ed. Shahidi, F.
AOCS Press, Champaign, IL. 1997, pp 12-24.
25. Pratt, D. E. Antioxidants indigenous to foods. In Antioxidants
Chemical, Physiological, Nutritional and Toxicological
Aspects. Ed., Williams, G. M. Princeton Scientific Publishing
Co. Inc. Princeton, NJ. 1993, pp 63-75.
26. Bracco, U., Loliger, J., Viret, J. L. Production and use of
natural antioxidants. J. Am. Oil Chem. Soc. 1981, 58, 686-
690.
10
AgroFOOD industry hi-tech

November/December 2006
27. Rababah T. M., Hettiarachchy, N. S., and Horax, R. Total
phenolics and antioxidant activities of fenugreek, green tea,

black tea, grape seed, ginger, rosemary, gotu kola, and
Anno 17 - No. 6
ginkgo extracts, vitamin E, and tert-butylhydroquinone. J.
Agric. Food Chem. 2004, 52, 5183-5186.
28. Nakatani, N., and Inatani, R. Two antioxidative diterpenes
from Rosemary (Rosemary officinalis L.) and a revised
structure of rosmanol. Agric. Biol. Chem. 1984, 48, 2081-
2085.
29. Houlihan, C. M., Ho, C. T., and Chang, S. S. Elucidation of
the chemical structure of a novel antioxidant isolated from
Rosmarinus officinalis L. J. Am. Oil Chem. Soc. 1984, 61,
1036-1039.
30. Houlihan, C. M., Ho, C. T., and Chang, S.S. The structure of
rosmariquinone- a new antioxidant isolated from
Rosmarinus officinalis L. J. Am. Oil Chem. Soc. 1985, 62, 96
98.
31. Hall III, C. A., Cuppett, S. L., and Dussault, P. Synthesis and
antioxidant activity of rosmariquinone and several
analogues. J. Agric. Food Chem. 1998a, 46, 1303-1310.
32. Schwarz, K. and Ternes, W. Antioxidative constituents of
Rosmarinus officinalis and Salvia officinalis. II. Isolation of
carnosic acid and formation of other phenolic diterpenes. Z
Lebensm Unters Forsch. 1992, 195, 99-103.
33. Schwarz, K., Ternes, W., and Schmauderer, E. Antioxidative
constituents of Rosmarinus officinalis and Salvia officinalis.
III. Stability of phenolic diterpenes of rosemary extracts
under thermal stress as required for technological
processes. Z Lebensm Unters Forsch. 1992, 195, 104-107.
34. Frankel, E.N., and Huang, S.W. Evaluation of antioxidant
activity of rosemary extracts, carnosol and carnosic acid in
bulk vegetable oils and fish oil their emulsions. J. Sci. Food
Agric. 1996, 72, 201-208.
35. Porter, W. L., Black, E. D., and Drolet, A. M. Use of
polyamide oxidative fluorescence test on lipid emulsions:
contrast in relative effectiveness of antioxidants in bulk vs
dispersed systems. J. Agric. Food Chem. 1989, 37, 615-
624.
36. Huang, S. W., Frankel, E. N., Aeschbach, R., and German,
J. B. Partition of selected antioxidants in corn oil-water
model systems. Rapid Communications. J. Agric. Food
Chem. 1997, 45, 1991-1994.
37. Hopia, A. I., Huang, S. W., German, J. B., and Frankel, E. N.
Effect of different lipid systems on antioxidant activity of
rosemary constituents carnosol and carnosic acid with and
without -tocopherol. J. Agric. Food Chem., 1996, 44, 2030-
2036.
38. Frankel, E. N., Huang, S.W., Aeschbach, R., and Prior, E.
Antioxidant activity of a rosemary extract and its
constituents, carnosic acid, carnosol and rosmarinic acid in
bulk oil and oil-in-water emulsion. J. Agric. Food Chem.
1996, 44, 131-135.
39. Chen, Q., Shi, H., and Ho, C.-T. Effects of rosemary extracts
and major constituents on lipid oxidation and soybean
lipoxygenase activity. J. Am. Oil Chem. Soc. 1992, 69, 999-
1002.
40. Hall III, C. A., Cuppett, S. L., and Dussault, P. Hydrogen-
donating mechanism of rosmariquinone, an antioxidant
found in rosemary. J. Am. Oil Chem. Soc. 1998b, 75, 1147-
1154.
41. Masuda, T., Inaba, Y., and Takeda, Y., Antioxidant
mechanism of carnosic acid: Structural identification of two
oxidation products. J. Agric. Food Chem. 2001, 49, 5560-
5565.
42. Singletary, K. W., and Rokusek, J. T. Tissue-specific
enhancement of xenobiotic detoxification enzymes in mice
by dietary rosemary extract. Plant Foods Hum. Nutr, 1997,
50, 47-53.
43. Huang, M. T., Ho, C. T., Wang, Z. Y., Ferraro, T., Lou, Y. R.,
Stauber, K., Ma, W., Georgiadis, C., Laskin, J.D., and
Conney, A. H. Inhibition of skin tumorigenesis by rosemary
and its constituents carnosol and ursolic acid. Cancer Res.
1994, 54, 701-708.
44. Singletary K. W., and Nelshoppen J. M. Inhibition of 7,12-
dimethylbenz[a]anthracene (DMBA)-induced mammary
tumorigenesis and of in vivo formation of mammary DMBA-
DNA adducts by rosemary extract. Cancer Lett, 1991, 60,
169-75.
45. Ninomiya, K., Matsuda, H., Shimoda, H., Nishida, N.,
Kasajima, N., Yoshino, T., Morikawa, T., and Yoshikawa, M.
Carnosic acid, a new class of lipid absorption inhibitor from
sage. Bioorg. Med. Chem. Lett. 2004, 14, 1943-1946.
46. Kosaka, K. and Yokoi, T. Carnosic acid, a component of
rosemary (Rosmarinus officinalis L.), promotes synthesis of
nerve growth factor in T98G human glioblastoma cells. Biol.
Pharm. Bull. 2003, 26, 1620-1622.