Antioxidants and free radicals
Most of today's degenerative diseases are at least partly due to free radical damage. Free radicals are highly unstable, "unfinished" molecules. In a normal living cell, they are formed when a chemical reaction is not completed. Free radicals attack sensitive structure in the cell -- such as DNA and lipids -- in a potentially devastating cascade reaction. Antioxidants capture the free radicals, thereby stopping the chain reaction and preventing further damage to the living cell.

Improving vision
• Night vision. Helps by stimulating the production of rhodopsin, also called eye purple, in the retina. The anthocyans are precursors to the rhodopsin, which is an essential element for night vision.
• Cataracts and macular degeneration. Growing evidence indicates that free radicals cause cataracts. That means that antioxidants may prevent them.
• Diabetic eye damage. The increased production of rhodopsin, combined with bilberry's capillary-protective effect, work together to improve eye integrity.
• Eye fatigue. It helps regenerate rhodopsin (retina's pigment). It improves circulation and the flow of nutrients to the eye. Its powerful antioxidants protect against the toxins in polluted air and possible radiation damage from the computer screen.

Circulatory effects
Bilberry interacts directly with collagen fibers, increasing the cross-link between them. Because of this effect on collagen, bilberry strengthens capillary permeability, preventing leakage. It can therefore dramatically improve peripheral circulation. The strengthening of capillaries helps prevent the aggravation of varicose veins. People prone to bruising will benefit from this also.

Grapeskin Chemistry
Oligomeric proanthocyanidins (OPCs) are oligomeric flavonoids, usually dimers, and trimers, based on the flavon-3-ol, or catechin molecule. OPCs are also found in grape skin, pine bark and cranberries and others.

OPCs exhibit the following properties:
(1) Antioxidant activity.
(2) Assist in collagen cross-linking.
(3) Sparing action on Vitamin C.

Pharmacological activity / Clinical benefits.

1. Protects LDL from oxidation - Oxidation of LDL is implicated in the development of atherosclerotic plaques.

2. Antiallergic / Anti-inflammatory activity. OPCs inhibit mast cell degradation (hence prevent the release of histamine, bradykinin and serotonin), which mediates inflammatory and allergic reactions, edema, and other conditions. OPCs also inhibit hyaluronidase activation. Hyaluronidase is a proteoglycan-splitting enzyme which can attack various tissues during inflammation and depolymerize hyaluronic acids, and is implicated in the permeability of the vascular system and the migration of metastases.

3. Vascular protection. OPCs have a particular affinity for the arterial walls and thus offer vascular protection. OPCs are potent inhibitors of elastic lamellal, and thus of the weakening of the vessel walls. In Europe, grapeseed extracts have been prescribed to prevent capillary fragility, to heal varicose veins and hemorrhoids and prevent edema.

4. Ulcer protection. OPCs are effective in preventing the formation of ulcers in animals. Flavonoids have been reported to provide significant protection against NSAIDs.

Reference

i. Mian E, Curri SB, Lietti A, Bombardelli E. "[Anthocyanosides and the walls of the microvessels: further aspects of the mechanism of action of their protective effect in syndromes due to abnormal capillary fragility]." Minerva Med 1977 Oct 31; 68(52): 3565-81.

ii. Hess HH, Knapka JJ, Newsome DA, Westney IV, Wartofsky L. "Dietary prevention of cataracts in the pink-eyed RCS rat." Lab Anim Sci 1985 Feb; 35(1): 47-53.

iii. Scharrer A, Ober M. "[Anthocyanosides in the treatment of retinopathies (author's transl)]" Klin Monatsbl Augenheilkd, 1981 May; 178(5): 386-9.

iv. Lietti A, Cristoni A, Picci M. "Studies on Vaccinium myrtillus anthocyanosides. I. Vasoprotective and antiinflammatory activity." Arzneimittelforschung 1976; 26(5): 829-32.

v. Galli RL, Shukitt-Hale B, Youdim KA, Joseph JA. "Fruit polyphenolics and brain aging: nutritional interventions targeting age-related neuronal and behavioral deficits." Ann N Y Acad Sci 2002 Apr; 959: 128-32.

Bilberry (Vaccinium myrtillus) anthocyanins modulate heme oxygenase-1 and glutathione S-transferase-pi expression in ARPE-19 cells.
Invest Ophthalmol Vis Sci. 2007 May;48(5):2343-9.
Milbury PE, Graf B, Curran-Celentano JM, Blumberg JB.

PURPOSE: To determine whether anthocyanin-enriched bilberry extracts modulate pre- or posttranslational levels of oxidative stress defense enzymes heme-oxygenase (HO)-1 and glutathione S-transferase-pi (GST-pi) in cultured human retinal pigment epithelial (RPE) cells.
METHODS: Confluent ARPE-19 cells were preincubated with anthocyanin and nonanthocyanin phenolic fractions of a 25% enriched extract of bilberry (10(-6)-1.0 mg/mL) and, after phenolic removal, cells were oxidatively challenged with H(2)O(2). The concentration of intracellular glutathione was measured by HPLC and free radical production determined by the dichlorofluorescin diacetate assay. HO-1 and GST-pi protein and mRNA levels were determined by Western blot and RT-PCR, respectively.
RESULTS: Preincubation with bilberry extract ameliorated the intracellular increase of H(2)O(2)-induced free radicals in RPE, though H(2)O(2) cytotoxicity was not affected. By 4 hours, the extract had upregulated HO-1 and GST-pi protein by 2.8- and 2.5-fold, respectively, and mRNA by 5.5- and 7.1-fold, respectively, in a dose-dependent manner. Anthocyanin and nonanthocyanin phenolic fractions contributed similarly to mRNA upregulation.
CONCLUSIONS: Anthocyanins and other phenolics from bilberry upregulate the oxidative stress defense enzymes HO-1 and GST-pi in RPE, suggesting that they stimulate signal transduction pathways influencing genes controlled by the antioxidant response element.


Effect of cyanidin-3-glucoside and an anthocyanin mixture from bilberry on adenoma development in the ApcMin mouse model of intestinal carcinogenesis--relationship with tissue anthocyanin levels.
Int J Cancer. 2006 Nov 1;119(9):2213-20.
Cooke D, Schwarz M, Boocock D, Winterhalter P, Steward WP, Gescher AJ, Marczylo TH.

Anthocyanins are dietary flavonoids, which can prevent carcinogen-induced colorectal cancer in rats. Here, the hypotheses were tested that Mirtoselect, an anthocyanin mixture from bilberry, or isolated cyanidin-3-glucoside (C3G), the most abundant anthocyanin in diet, interfere with intestinal adenoma formation in the Apc(Min) mouse, a genetic model of human familial adenomatous polyposis, and that consumption of C3G or Mirtoselect generates measurable levels of anthocyanins in the murine biophase. Apc(Min) mice ingested C3G or Mirtoselect at 0.03, 0.1 or 0.3% in the diet for 12 weeks, and intestinal adenomas were counted. Plasma, urine and intestinal mucosa were analyzed for presence of anthocyanins by high-pressure liquid chromatography with detection by UV spectrophotometry (520 nm) or tandem mass spectrometry (multiple reaction monitoring). Ingestion of either C3G or Mirtoselect reduced adenoma load dose-dependently. At the highest doses of C3G and Mirtoselect adenoma numbers were decreased by 45% (p < 0.001) or 30% (p < 0.05), respectively, compared to controls. Anthocyanins were found at the analytical detection limit in the plasma and at quantifiable levels in the intestinal mucosa and urine. Anthocyanin glucuronide and methyl metabolites were identified in intestine and urine. Total anthocyanin levels in mice on C3G or Mirtoselect were 43 ng and 8.1 microg/g tissue, respectively, in the intestinal mucosa, and 7.2 and 12.3 microg/ml in the urine. The efficacy of C3G and Mirtoselect in the Apc(Min) mouse renders the further development of anthocyanins as potential human colorectal cancer chemopreventive agents worthwhile.


[Anthocyanosides and the walls of the microvessels: further aspects of the mechanism of action of their protective effect in syndromes due to abnormal capillary fragility]
Minerva Med 1977 Oct 31; 68(52): 3565-81. [Article in Italian]
Mian E, Curri SB, Lietti A, Bombardelli E.

On the basis of previous biochemical observations, which have demonstrated the formation of complexes between anthocyanosides and some phospholipids, the AA. investigate the modifications induced by local and general administration of anthocyanosides 1) on the foreign body granuloma and 2) on the composition of the protein fractions in the exudate from the capillaries of the granulation tissue, growing on post-thromboflebitic or varicose leg ulcerations. The biochemical and histochemical data may show that the anthocyanosides protect the altered capillary walls with a double mechanism: a) increasing the endothelium barrier-effect through a stabilisation of the membrane phospholipids and b)increasing the biosynthetic processes of the acid mucopolysaccharides of the connective ground substance, by restoring the altered mucopolysaccharidic pericapillary sheat. This last effect may explain the marked increase of new-formed capillaries and collagen fibrils induced by the anthocyanosides.


Dietary prevention of cataracts in the pink-eyed RCS rat.
Lab Anim Sci 1985 Feb; 35(1): 47-53.
Hess HH, Knapka JJ, Newsome DA, Westney IV, Wartofsky L.

The American Institute of Nutrition purified ingredient diet (AIN-76) prevented occurrence of mature cataracts associated with hereditary retinal degeneration in pink-eyed, tan-hooded Royal College of Surgeons (RCS) rats. Rats fed a natural ingredient open formula NIH diet or a closed formula commercial diet had a cataract incidence of 27-29% by 3 to 12 months of age. In contrast, only 1 of 50 rats fed the AIN diet developed a mature cataract in one year. When the NIH diet and the commercial diet were pelleted with 25% of ground sunflower kernels, rats fed these diets had a delay in onset and a reduced incidence of mature cataracts to 18% and 5%, respectively. No mature cataracts occurred in rats fed the AIN diet supplemented with 25% sunflower kernels. All diets were fed to the parental generation as well as the progeny (experimental group). The rats werereared at a low level of illumination (1-3 footcandles inside the cage) to minimize effects of light. Prevention of mature cataracts by the AIN purified diet suggests that diets permitting cataracts to occur may have a constituent at a concentration innocuous for normal rats but beyond the homeostatic control of the RCS rat. Posterior subcapsular cataracts of RCS rats are a model for cataracts associated with human hereditary retinal degenerations, such as retinitis pigmentosa and gyrate atrophy. Manipulation of dietary ingredients allowed by the use of the AIN diet may permit identification of nutrients, nutrient interactions of toxic factors involved in cataractogenesis and its prevention.


[Anthocyanosides in the treatment of retinopathies (author's transl)]
Klin Monatsbl Augenheilkd 1981 May; 178(5): 386-9. [Article in German]
Scharrer A, Ober M.

Thirty-one patients with various types of retinopathy were investigated with regard to the effect of anthocyanosides on the retinal vessels. Especially in patients with diabetic retinopathy, a positive influence on the permeability and tendency to hemorrhage was observed. The importance of internal treatment of the primary disease is pointed out.


Studies on Vaccinium myrtillus anthocyanosides. I. Vasoprotective and antiinflammatory activity.
Arzneimittelforschung 1976; 26(5): 829-32.
Lietti A, Cristoni A, Picci M.

A Vaccinium myrtillus anthocyanosides preparation (equivalent to 25% of anthocyanidins) demonstrated significant vasoprotective and antioedema properties in exerimental animals. In rabbits, the skin capillary permeability increase, due to chloroform, was reduced both after i.p. (25--100 mg/kg) and oral administration (200--400 mg/kg) of anthocyanosides. Their activity was more lasting in comparison to rutin or mepyramine and this did not seem to be due to a specific antagonism towards inflammatory process mediators such as histamine or bradykinin. Experiments carried out in rats demonstrated that Vacinium myrtillus anthocyanosides were effective both in skin capillary permeability test as well as on vascular resistance of rats fed a P factor deficient diet. In the former test effective doses were in the range of 25--100 mg/kg (by oral route). In both the animal species investigated, anthocyanosides were two-fold more active when compared to the flavonoid rutin. Vaccinium myrtillus anthocyanosides by oral route inhibited carrageein paw oedema in rats showing a dose-response relationship. An antioedema activity was detected also after i.v. or topical application.


Fruit polyphenolics and brain aging: nutritional interventions targeting age-related neuronal and behavioral deficits.
Ann N Y Acad Sci 2002 Apr; 959: 128-32.
Galli RL, Shukitt-Hale B, Youdim KA, Joseph JA.

Nutritional interventions, in this case, increasing dietary intake of fruits and vegetables, can retard and even reverse age-related declines in brain function and in cognitive and motor performance in rats. Our lab has shown that as Fischer 344 rats age their brains are increasingly vulnerable to oxidative stress. Dietary supplementation with fruit or vegetable extracts high in antioxidants (e.g., blueberry, BB, spinach, respectively) can decrease this vulnerability to oxidative stress as assessed in vivo by examining reductions in neuronal signaling and behavioral deficits and in vitro via H2O2-induced decrements in striatal synaptosomal calcium buffering. Examinations have also revealed that BB supplementations are effective in antagonizing other age-related changes in brain and behavior, as well as decreasing indices of inflammation and oxidative stress in gastrocnemius and quadriceps muscles. In ongoing studies we are attempting to determine the most effective BB polyphenolic components. To date, the anthocyanins show the most efficacy in penetrating the cell membrane and in providing antioxidant protection. In sum, our results indicate that increasing dietary intake of fruits and vegetables high in antioxidant activity may be an important component of a healthy living strategy designed to maximize neuronal and cognitive functioning into old age.