The most characteristic compounds present in bilberry fruits are colorful
polyphenols belonging to the classes of anthocyanins-
and of proanthocyanidins.
The pharmacological properties of these substances seem nowadays well ascertained; they are mainly linked to a strong antioxidant capacity, although associated with many other biological activities, such as anti-inflammatory, vasoactive, hypolipemic, hypoglycemic, cell-regenerating, antimicrobial, chemopreventive, etc. Almost all of these properties have been intensively studied, both in vitro and in vivo.
Bilberry anthocyanins and some related aglycones are reported to be potent
scavengers of free radicals, as when tested in vitro in the superoxide anion
generating system hypoxanthine/xanthine oxidase.(1,2)
Anthocyanin extracts of Vaccinium myrtillus fruits have been shown to
act both as scavengers against superoxide anion and as inhibitors of lipid
peroxidation in rat liver microsomes.(3-5)
Cyanidin and delphinidin chlorides proved to be potent scavengers, interacting with 1,1-diphenyl-1-picrylhydrazyl (DPPH) free radical: the IC50 values were 2.5 and 4.0 µM, respectively, comparable to that of quercetin.
Cyanidin chloride is the most active compound on CCl4 induced lipoperoxidation.(6)
Laplaud et al.(7) reported that an aqueous extract of V. myrtillus berries protected low-density lipoproteins (LDL) from copper-mediated oxidation.
As reported by Rasetti et al.(8) a proprietary Bilberry extract was capable of protecting apolipoprotein B from UV-induced oxidative fragmentation.
Ichiyanagi et al.(9) studied the activity of 11 major bilberry anthocyanins against hydroxyl radicals (OH°), superoxide anion, and singlet oxigen by using capillary zone electrophoresis. The reactivity of anthocyanins towards OH° was comparable to that of (+)-catechin used as reference substance, and was neither significantly affected by the aglycon structure nor by the conjugated sugar type. On the contrary, the reactivity towards superoxide anion and singlet oxygen were determined by the aglycon structure.
K. Nakanishi et al.(10) have demonstrated that anthocyanins-rich bilberry extracts can prevent the light-induced photo-oxidation of A2E, the major eye lipofuscin. Lipofuscins, a class of orange and fluorescent pigments, accumulate with age in retinal epithelium, and are therefore also known as "age pigments". They have been suggested to play a critical role in the pathogenesis of age-related macular degeneration (AMD), the major cause of blindness in industrialized countries. When exposed to light, lipofuscins generate singlet oxygen, a reactive oxygen species that trigger degeneration of the visual epithelium. This process was suppressed by bilberry anthocyanins, and protection from retinal photo-oxydation might be an important mechanism for the eye beneficial effects of bilberry anthocyanins.
In a more recent study on gene expression determined by microarray analysis, it was shown that Mirtoselect® anthocyanins can attenuate the expression level of pro-inflammatory genes and restore that of anti-inflammatory genes in an inflammatory cell model, providing a rationale for the anti-inflammatory activity of bilberry anthocyanosides(11). A catechol moiety on ring B was found critical for the anti-inflammatory activity of anthocyanins(12). Remarkably, 80% of the anthocyanins of Mirtoselect® belong to this structural type.
Prior et al.(13) comparing the antioxidant capacity (oxygen radical absorbance capacity, ORAC) of different variety of four Vaccinium species found that V. myrtillus and V. angustifolium (low bush) exhibited potent ORAC activity (44.6±2.3 and 45.9±2.2, respectively).
A linear relationship existed between ORAC and anthocyanins (rxy = 0.77) or total phenolic content (rxy = 0.92).
Anthocyanins can also prevent the oxidation of ascorbic acid caused by metal ions by chelating the metals ions and forming an ascorbic acid (copigment)-metal-anthocyanin complex.(14) In addition the anthocyanins extract is reported to inhibit the K+ loss induced by free radicals in human erythrocytes as well as the cellular reactions induced by the oxidative compounds daunomycin and paraquat.(15,16).
Most recent studies(17) indicate that Mirtoselect® is active in protecting the kidneys form damage induced by potassium bromate in mice. Potassium bromate is an environmental pollutant, which can be formed as a by-product in the process of ozone purification of drinking water. It may form free radicals triggering harmful modifications in the kidney tissue.
The protective properties of bilberry extract are due to the improved antioxidant capacity of the kidney tissue promoted by bilberry anthicyanins: the reduction of NO production and the improved ability to absorb oxygen radical (ORAC).
Li Bao et al.(18) showed that Mirtoselect® is able to alleviate stress-induced liver damage in mice by both scavenging free radicals activity and lipid peroxidation inhibitor effect. In a following study(19) the same group showed that Mirtoselect® restored alanine aminotransferase (ALT) and reactive oxygen species (ROS) to normal levels, and enhanced mitochondrial complex II activity that was lowered in the experimental conditions.
In a recent study in mice Endotoxin-induced uveitis (EIU)(20), Mirtoselect®, has been shown to reduce levels of nitric oxide and malondialdehyde in eyes and to elevate ORAC, glutathione, vitamin C, superoxide dismutase, glutathione peroxidase activity in eyes. Moreover, Mirtoselect® increased expression of copper/zinc superoxide dismutase, manganese superoxide dismutase, and glutathione peroxidase mRNA, indicating that Mirtoselect® could attenuate inflammation-induced oxidative stress in EIU by increasing levels of antioxidants.
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2. Acquaviva R., Russo A., Galvano F., Galvano G., Barcellona M.L., Li Volti G., Vanella A., "Cyanidin and cyanidin 3-O-beta-D -glucoside as DNA cleavage protectors and antioxidants", Cell. Biol. Toxicol. 19, 243 (2003).
3. Meunier M.T., Duroux E., Bastide P., Plant médicin. Phytothér. 23, 267 (1989).
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8. Rasetti M.F., Caruso D., Galli G., Bosisio E., Phytomedicine 3, 335 (1996/97).
9. Ichiyanagi T., Hatano Y., Matsugo S., Konishi T., "Kinetic comparisons of anthocyanin reactivities towards 2,2'-azobis(2-amidinopropane) (AAPH) radicals, hydrogen peroxide and tert-buthylhydroperoxide by capillary zone electrophoresis", Chem Pharm Bull (Tokyo). 2004 Apr;52(4):434-8.
10. Sparrow JR, Vollmer-Snarr HR, Zhou J, Jang YP, Jockusch S, Itagaki Y, Nakanishi K. A2E-epoxides damage DNA in retinal pigment epithelial cells. Vitamin E and other antioxidants inhibit A2E-epoxide formation. J. Biol. Chem., Vol. 278, Issue 20, 18207-18213 (2003).
11. Chen, Jihua, Uto, Takuhiro, Tanigawa, Shunsuke, Kumamoto, Takuma, Fujii, Makoto and Hou, De-Xing. "Expression Profiling of Genes Targeted by Bilberry (Vaccinium myrtillus) in Macrophages Through DNA Microarray", Nutrition and Cancer, 60:1,43 - 50 (2008).
12. Hou DX, Yanagita Y, Uto T, Masuzaki S, and Fujii, M. "Anthocyanidins inhibit cyclooxygenase-2 expression in LPS-evoked macrophages: structure-activity relationship and molecular mechanisms involved. Biochem Pharmacol 70, 417–425, 2005.
13. Prior R.L., Cao G., Martin A., Sofic E., McEwen J., O’Brien C., Lischner N., Elhenfeldt M, Kalt W., Krewer G., Mainland C.M., J. Agric. Food Chem. 46, 2686 (1998).
14. Sarma A.D., Sreelakshmi Y., Sharma R., Phytochemistry 45, 671 (1997).
15. Maridonneau I., Braquet P., Garay R.P. in "Flavonoids and Bioflavonoids, 1981", L. Farkas, M. Gábor, F. Kállay, H. Wagner (Eds), Elsevier, Amsterdam, 1982, pp 427-436.
16. Mavelli I., Rossi L., Autuori F., Braquet P., Rotilio G., in "Oxy Radicals Their Scavenger Syst.", Proc. Int. Conf. Superoxide Dismutase, 3dr 1982 , G. Cohen , R.A. Greenwald , Elsevier, New York, 1983, pp 326-329.
17. Bao L., Yao XS., Tsi D., Yau CC., Chia CS., Nagai H., Kurihara H., "Protective effects of bilberry (Vaccinium myrtillus L.) extract on KBrO3-induced kidney damage in mice", J. Agric. Food Chem., 56, pag. 420-425 (2008)
18. Li Bao, Xin-Sheng Yao, Chin-Chin Yau, Daniel Tsi, Chew-Sern Chia, Hajme Nagai, Hiroshi Kurihara, "Protective effects of bilberry (Vaccinium myrtillus L.) extract on restraint stress-induced liver damage in mice" J. Agric. Food Chem., Published on Wed August 9, 2008.
19. Bao L, Abe K, Tsang P, Xu JK, Yao XS, Liu HW, Kurihara H. Bilberry extract protect restraint stress-induced liver damage through attenuating mitochondrial dysfunction, Fitoterapia. Volume 81, Issue 8, December 2010, Pages 1094-1101
20. Yao N. Protective effects of bilberry (Vaccinium myrtillus L.) extract against Endotoxin-induced uveitis in mice. J. Agric. Food Chem., 2010, 58 (8), pp 4731–4736