INDEX

Bilberry

(Source: SaluGenecists, Inc.)

Summary

Bilberry, is a member of the genus Vaccinium, which contains hundreds of species, many of which produce edible berry-like fruits with medicinal properties; other examples of plants within this genus are the American cranberry (Vaccinium macrocarpon) and blueberry (Vaccinium myrtillus). Bilberry grows abundantly in the woods and forest meadows of Europe and in heathy mountainous areas in the northern United States.

Bilberry is a small-branched perennial shrub that bears reddish or greenish-pink flowers and blue-black berries. Both the bilberry fruit and the leaves are used medicinally. The fruit is oftentimes used in the forms of decoctions, liquid extracts, and tablets while the leaf is usually prepared as tea.

Bilberries have enjoyed a long history as both food and medicine. Since they have high nutritive value, rich juice and miniature seeds, they have been long used to make jams and jellies. Their history of medicinal use dates back to antiquity with the ancient Greek Dioscorides using them to treat diarrhea and dysentery.

Flavonoids, specifically anthocyanosides, are the most pharmacologically active constituents in bilberry fruit. In addition to anthocyanosides, bilberry fruit also contains catechin, epicatechin, condensed tannins, oligomeric procyanidins, and pectins. The active constituents isolated from the leaf of the bilberry plant include quercetin, catechins, tannins and iridoids.

Research on bilberrys pharmacological effects has focused primarily on the effects of its anthocyanosides on collagen and blood vessels. Extracts containing anthocyanosides have been shown to promote the biosynthesis of collagen and prevent its destruction. Additionally, they can decrease capillary permeability and fragility, prevent edema, and inhibit platelet aggregation. With strong antioxidant actions, they have the ability to protect LDL cholesterol from oxidative stress.

Bilberry anthocyanosides have demonstrated strong anti-inflammatory actions including preventing the release and synthesis of pro-inflammatory compounds such as histamine, prostaglandins, and leukotrienes. Compounds in bilberry extract have also been found to exert anti-carcinogenic activity and also increase gastric mucus production while bilberry leaf decoctions have been shown to lower blood glucose levels.

The primary clinical application for bilberry extracts has been in the prevention and treatment of opthamological disorders including glaucoma, cataracts, diabetic retinopathy, day blindness and night vision improvement. Since capillary dysfunction and inflammation also play a role in wound healing, diabetes mellitus and inflammatory joint diseases, bilberry is also used for these conditions.

Extensive toxicological investigations have demonstrated that bilberry anthocyanoside extracts are devoid of toxic effects. Bilberry fruit consumption is very safe, and virtually no side effects have been reported.

Although no drug/nutrient/herb interactions are known to occur with bilberry fruit, theoretically, very high doses could interact with warfarin and antiplatelet drugs and should be used cautiously in patients with hemorrhagic disorders. As preliminary evidence suggests that bilberry leaf might lower blood glucose, diabetes drugs might require dosing adjustment if bilberry leaf is used.

Typical dosage varies depending upon the form being used and the health care application for which it is being used.

Key Constituents

Bilberry fruits flavonoid components, specifically its anthocyanosides, are its most pharmacologically active constituents. Anthocyanosides, also known as anthocyanins, are composed of an aglycone (e.g., anthocyanidin) bound to one of three glycosides (arabinoside, glucoside, or galactoside). Bilberry contains five aglycones, which bind to glycosides forming more than 15 different anthocyanosides, including C-3 glucosides of delphinidin, malvidin, pelargonidin, cyanidin, and petunidin.

In the fresh bilberry fruit, the concentration of anthocyanosides is approximately 0.10.25%.

Concentrated extracts yield an anthocyanidin content of 25%. (An extract with an anthocyanidin content of 25% actually contains about 37% anthocyanosides due to the conjugation of the anthocyanidin with a glycoside. Only very small amounts of free anthocyanidins exist in nature and in Vaccinium myrtillus extracts.) In addition to its anthocyanosides, bilberry fruit also contains:

  • catechin, epicatechin, condensed tannins, oligomeric procyanidins (procyanidin B1-B4)
  • flavonoids, phenolic acids, pectins

Several active constituents have also been isolated from the leaf of the bilberry plant, including:

  • quercetin
  • catechins
  • tannins
  • iridoids
  • acids

The berry’s anthocyanoside content increases as the fruit ripens, while the reverse is true of the active constituents in the leaf.

Historical Use

Bilberries have long been valued as both food and medicine. Owing to their high nutritive value, rich juice and the minuteness of their seeds, they remain a precious wild delicacy valued for its use to produce exceptional jams. Medicinally, bilberrys astringent qualities were noted by the ancient Greek, Dioscorides who used them to treat diarrhea and dysentery. In the 16th century, bilberries use was documented for drying up breast milk and in the treatment of hemorrhoids, vaginal discharges, scurvy, biliary disorders, coughs, lung tuberculosis, and urinary complaints (including infection and stones). Decoctions of bilberry leaf have been used to lower blood sugar in the treatment of diabetes, and as a local application to ulcers, and in ulceration of the mouth and throat. Current research has focused on the effects of bilberrys active constituents, primarily its anthocyanosides, in the treatment of ocular disorders, vascular disorders and diabetes mellitus.

Physiological Effects

Collagen-stabilizing Activities

Anthocyanosides have demonstrated significant collagen-stabilizing action in vitro. Collagen, the bodys most abundant protein, provides and maintains the integrity of ground substance as well as tendons, ligaments, and cartilage. The destruction of collagen is a side-effect of the inflammatory processes that occur in rheumatoid arthritis, periodontal disease, and other inflammatory conditions involving bones, joints, cartilage, and other connective tissue. Bilberry contains not only anthocyanidins, but proanthocyanidins and other flavonoids, all of which effectively prevent collagen destruction. The anthocyanosides in bilberry extracts have been shown to affect collagen metabolism in several ways:

  • Anthocyanosides cross-link collagen fibers, strengthening the natural cross-linking of collagen that forms the collagen matrix of connective tissue (ground substance, cartilage, tendon, etc.).
  • Anthocyanosides powerful antioxidant and free-radical scavening actions protect collagen against free radical damage.
  • Anthocyanosides protect collagen against non-enzymatic proteolytic activity and also inhibit enzymatic cleavage by enzymes secreted by leukocytes during inflammation.
  • Anthocyanosides and other flavonoids in bilberry prevent the release and synthesis of proinflammatory compounds including histamine, serine proteases, prostaglandins, and leukotrienes.
  • Anthocyanosides stimulate mucopolysaccharide and collagen biosynthesis and reticulation of collagen fibrils.

Normalization of Capillary Permeability

Anthocyanosides have demonstrated significant vasoprotective activity on microcirculation and have been shown to be more effective than flavonoids in protecting damaged capillaries and to stimulate capillary repair. Included in their effects are an ability to increase intracellular vitamin C levels, decrease capillary permeability and fragility, prevent leucocyte adhesion after ischemia and reperfusion, prevent interstitial fluid formation and edema, and improve capillary perfusion.

Anthocyanosides effect in reducing capillary fragility and permeability is roughly twice as strong as that of rutin, in both intensity and duration of activity. Anthocyanosides effects are not due to specific antagonism of inflammatory mediators such as histamine or bradykinin, as are the effects mediated by most flavonoids, e.g., rutin. but are the result of their numerous stabilizing interactions with collagen in blood vessel walls.

Improvement in Venous Strength and Function

Bilberry exctracts have been widely used in Europe for the treatment of venous disorders due to the efficacy of anthocyanosides in protecting damaged veins (varicose and postphlebotic veins) via two mechanisms:

  • stabilizing membrane phospholipids, thus improving the strength and function of the endothelium barrier.
  • increasing the biosynthesis of the acid mucopolysaccharides of the connective ground substance, which leads to restoration of the damaged mucopolysaccharide pericapillary sheath and a marked increase in the formation of new capillaries and collagen fibrils.

Decreasing Blood-brain Barrier Permeability

Bilberry extracts normalization of collagen structures and capillaries also results in a decrease in the permeability of the bloodbrain barrier. Increased bloodbrain permeability has been linked to a variety of CNS disorders including autoimmune diseases of the central nervous system, schizophrenia, and cerebral allergies. The anthocyanosides likely mechanism of action is their inhibition of both enzymatic and non-enzymatic degradation of brain capillaries basement membrane collagen. The resulting improvement in brain capillary function helps maintain or restore the brains protection from cerebral toxins including drugs, pollutants, and naturally occurring degradation products.

Inhibition of Platelet Aggregation

Bilberry extracts have demonstrated significant inhibitiory effects on platelet aggregation in humans when given at doses of 480 mg per day for 30-60 days. The mechanism of action in vivo appears to be due to an increase in the concentration of cAMP and/or a decrease in the concentration of platelet thromboxane. Anthocyanosides (cyanidin, delphinidin and malvidin 3-O-glucosides) and their aglycones have been shown to inhibit phosphodiesterases. Inhibition of phosphodiesterase leads to increased cyclic AMP and cyclic GMP in tissue. cAMP prevents platelets from aggregating and adhering to the endothelial surface.

Anti-inflammatory, Anti-edema Vascular Effects

In animal studies, bilbery extract (72-144 mg/kg anthocyanidins) has demonstrated significant vasoprotective and anti-edema effects in vivo. These effects were not due to inhibition of inflammatory mediators such as histamine or bradykinin, but are thought to result from anthocyanidins interaction with collagen within blood vessel walls. In a preliminary human study, women with dysmenorrhea were given bilberry extract (115 mg anthocyanosides per day) for three days prior to and during menstruation. A significant lessening in pelvic/lumbosacral pain, mammary tension, nausea, and lower-limb heaviness was noted.

Anticarcinogenic Activity

The hexane/chloroform subfraction of bilberry ethyl acetate and the proanthocyanidin fraction of bilberry extract have been found to exhibit anticarcinogenic activity. Bilberry crude extract was screened for anticarcinogenic compounds by in vitro testing of its ability to induce the Phase II xenobiotic detoxification enzyme quinone reductase and to inhibit the induction of ornithine decarboxylase (the rate-limiting enzyme in polyamine synthesis), by the tumor promoter phorbol 12-myristate 13-acetate.

The ethyl acetate extracts, but not the anthocyanin and proanthocyanidin fractions, were highly active in inducing quinone reductase. Further fractionation of the bilberry ethyl acetate extract revealed that the majority of inducer potency was contained in a hexane/chloroform subfraction.

Crude extracts of bilberry were found to inhibit ornithine decarboxylase activity by 50% at a concentration of 8.0 micrograms tannic acid equivalents. The fractions with the most inhibitory activity were the polymeric proanthocyanidin fractions of bilberry fruit, which inhibited ornithine decarboxylase activity by 50% at a concentration of 3.0 micrograms tannic acid equivalents.

Anti-ulcer Activity

The antiulcer activity of an anthocyanoside in bilberry, cyanidin chloride, has been demonstrated in various experimental models. Magistretti et al demonstrated that cyanidin chloride increases gastric mucus production without affecting gastric secretion. In Sprague Dawley and Wistar rats, bilberry extract (equivalent to 9-72 mg/kg anthocyanins) has also demonstrated significant dose-dependent antiulcer activity and decreased the incidence and severity of numerous forms of experimentally induced ulcers.

Antioxidant Activity

In a number of in vitro models, bilberry extract, specifically its anthocyanosides, have been shown to produce significant antioxidant activity including the ability to:

  • scavenge superoxide anions
  • inhibit the potassium ion loss induced by free radicals in human erythrocytes
  • inhibit cellular reactions induced by oxidant compounds
  • inhibit lipid peroxidation
    • inhibition of oxysterol formation (cholesterol oxides) after photo-induced oxidation of LDL. (Oxysterols are primary contributors to the atherogenicity and cytotoxicity of oxidized LDL.)
    • protection of LDL particles during copper-mediated oxidation. (This was accomplished using only trace amounts of aqueous bilberry extract (15 to 20 mcg/mL); therefore, the extract may be even more potent than ascorbic acid in protecting LDL from oxidative stress.)
      protect LDL via several mechanisms including

Wound-healing Activity

Applied topically, bilberry was found to accelerate the process of spontaneous healing of experimental skin wounds whose healing had been delayed by a steroidal antiinflammatory agent.

Typical Use

The primary clinical application of bilberry extracts has been in the prevention and treatment of opthamological disorders. However, the same mechanisms of action that benefit the eye are also effective in the treatment of virtually all disorders in which capillary dysfunction or inflammation plays a significant role including diabetes, ulcers, and schizophrenia, and in inflammatory conditions involving connective tissues (e.g., osteoarthritis, gout, rheumatoid arthritis, periodontal disease, etc.).

Night Vision and Day Blindness

Anecdotal reports of RAF pilots using bilberry to improve their night vision aroused interest that led to a series of studies in which the administration of bilberry extract to healthy subjects resulted in improved night-time visual acuity, quicker adjustment to darkness, and faster restoration of visual acuity after exposure to glare. In placebo-controlled trials, individuals taking anthocyanins demonstrated significantly better night vision than those taking placebo. In uncontrolled trials involving air-traffic controllers, pilots and automobile drivers, bilberry extract improved night vision.

Further studies involving individuals with ocular disorders confirimed the beneficial effects seen in healthy subjects. The most impressive benefit was seen in individuals with pigmentary retinitis and hemeralopia (day blindness or an inability to see as distinctly in bright as in dim light). In vitro clinical effects demonstrate that, in addition to anthocyanosides positive effects on capillaries, they also have an affinity for the pigmented epithelium of the retina, the optical or functional part of the retina. Bilberry has been shown to hasten the regeneration of rhodospin (visual purple) after injection. Rhodospin is a light-sensitive pigment found in the rods of the retina that must be quickly regenerated to maintain visual sensitivity.

Glaucoma

Bilberrys antioxidant properties and beneficial effects on collagen structures in the eye may make a significant contribution to the prevention and treatment of glaucoma. In all ocular tissues, e.g., the cornea, sclera, lamina cribosa, trabecular meshwork, vitreous, etc., collagen provides tensile strength and integrity. Morphological changes in ocular collagen precede clinically detectable abnormalities. The reduced tensile strength and integrity of aging eye tissue may result from changes in ocular collagen that lead to elevated intraocular pressure (IOP) and/or the progression of peripheral vision loss. Loss of ocular collagen integrity would explain why in glaucoma:

  • similar peripheral vision loss is found in patients with normal and elevated IOP
  • cupping of the optic disc occurs even at low IOP levels
  • decreased aqueous outflow occurs without an apparent anatomical reason

All these deleterious symtoms involve disruption of ground substance and collagen framework integrity. Preventing collagen matrix breakdown is therefore essential in the both prevention and treatment of glaucoma, as it is in other conditions involving collagen abnormalities, e.g., atherosclerosis, rheumatoid arthritis, and periodontal disease.

The anthocyanosides found in bilberry may offer not only significant protection against the development of glaucoma, but may also be of benefit in the treatment of chronic glaucoma due to their collagen-enhancing actions. The activity of bilberrys anthocyanosides has been shown to be stronger and longer-lasting that that of rutin, which has been demonstrated to lower IOP when used as an adjunct in patients unresponsive to miotics alone. In one study, eight patients with glaucoma who were given a single oral dose of bilberry anthocyanosides (200 mg) demonstrated improvement based on electroretinography. Anthocyanosides collagen-stabilizing effect on the trabecular meshwork, which would facilitate aqueous outflow, is a likely mechanism.

Cataracts and Retinal Degeneration

Bilberry anthocyanosides may offer significant protection against the development of retinal (macular) degeneration and cataracts, particularly diabetic retinopathy and cataracts. Studies have demonstrated that diets high in anthocyanoside flavonoids retard both the rate of retinal degeneration and the occurrence of cataracts in rats. In a human clinical study in which bilberry extract (180 mg twice daily of a 25-percent anthocyanoside extract) was given with vitamin E, cataract formation was arrested in 48 of 50 patients with senile cortical cataracts.

Diabetic Retinopathy

Bilberry anthocyanoside extracts are widely used in Europe in the prevention of diabetic retinopathy, with several clinical trials supporting this use. In one month-long double-blind study, 14 patients with diabetic and/or hypertensive retinopathy were given bilberry extract equivalent to 115 mg anthocyanosides or placebo daily. Significant improvements were observed in the ophthalmoscopic parameters of 11 subjects receiving bilberry, and 12 patients showed improvement in angiographic parameters.

The positive effects noted in this and other clinical trials are likely due to bilberry anthocyanosides ability to increase intracellular vitamin C levels, thus reducing sorbitol accumulation as well as improving capillary integrity. Sorbitol is a by-product of glucose metabolism that is normally metabolized by polyol dehydrogenase to fructose, which can be excreted from the cell. In diabetics, frequent hyperglycemia results in sorbitol accumulation that creates an osmotic gradient that draws water into the cell to maintain osmotic balance. As water comes in, the cell also releases small molecules like glutathione, vitamin C, magnesium and potassium. Since these compounds are involved in activities that protect the lens from damage, the delicate proteins in the retina are more susceptible to damage. Both vitamin C and flavonoids have been shown to be potent in vitro and in vivo inhibitors of sorbitol accumulation. In laboratory experiments, they have been shown capable of inhibiting the development of diabetic cataracts.

Diabetes Mellitus

Bilberry leaf decoctions have a long history of folk use in the treatment of diabetes. Research has shown that oral administration of bilberry leaf decoctions reduces hyperglycemia in normal and depancreatized dogs, even when glucose is given intravenously concurrently. This effect is attributed to the myrtillin anthocyanoside (3-glucoside of delphinidin), the most active hypoglycemic component in bilberry. Although bilberry leaf is somewhat weaker than insulin, it is less toxic, even at 50 times the 1 g/day therapeutic dose. In addition, a single dose can produce beneficial effects lasting for several weeks.

Bilberry fruit anthocyanosides provide even more important benefit due to their ability to improve collagen integrity, normalize capillary permeability, and inhibit sorbitol accumulation, thus providing protection against the deleterious vascular and neurological sequelae of diabetes.

Bilberry anthocyanosides have also been shown to have a protective effect on capillary fragility in diabetics and to reduce serum cholesterol and triglyceride levels in primary dyslipidemia.

Although studies in rabbits have not confirmed a cholesterol-lowering effect, bilberry anthocyanosides have been shown to significantly decrease the intimal proliferation. extracellular matrix production, and calcium and lipid deposition found in the aorta of untreated atherosclerotic rabbits. The protective mechanism resposible is likely anthocyanosides effect of increasing collagen cross-linking, thus diminishing permeability in small, as well as in large, blood vessels.

Vascular Disorders

Bilberry extracts are widely used in Europe in the treatment of various arterial, venous, and capillary disorders. Clinical studies have demonstrated positive benefit in the treatment of:

  • capillary fragility
  • blood purpuras (hemorrhages into the skin, mucous membranes, internal organs and other tissues. In the skin, these manifest as red discolorations that darken to purple, then fade to yellow and disappear in 2-3 weeks).
  • various encephalic circulation disturbances
  • venous insufficiency
  • varicose veins
  • microscopic hematuria caused by diffused and kidney capillary fragility

Inflammatory Joint Disease

The combination of anthocyanosides effects on collagen structures and potent antioxidant activity render bilberry extracts useful in the treatment of many inflammatory conditions, most notably rheumatoid arthritis. Bioflavonoids have been found to increase collagen synthesis and inhibit collagen catabolism in rats with adjuvant-induced arthritis (a chronic progressive polyarthritis with some similarities to rheumatoid arthritis).

The enzyme xanthine oxidase catalyses the oxidation of hypoxanthine to xanthine and then to uric acid, which plays a crucial role in gout. A recent study revealed xanthine oxidase inhibitory activity in a number of North American plants traditionally used for gout. The most inhibition was found in plants with the highest levels of phenols and tannins. Bilberries, like cherries, are also particularly beneficial in the treatment of gout, as not only do their flavonoids, phenolic acids and tannins effectively reduce uric acid levels, but their anthocyanosides antioxidant and antiinflammatory actions also help to prevent tissue destruction.

Typical Use

  • Fruit (dried or fresh)
    • Decoction, prepared by placing 5-10 grams (1-2) teaspoons) of mashed berries in cold water, then bringing to a simmer to 10 minutes, then straining the water.
    • Liquid extract
    • Tablets

     

  • 1-2 teaspoons of finely chopped leaf steeped in 150 mL boiling water for 5-10 minutes, then strained. (Only for short term use.)
    Leaf

Interactions

Bilbery fruit

No interactions are known to occur.

Theoretically, very high doses could interact with warfarin and antiplatelet drugs.

Bilberry leaf

Blood glucose lowering drugs: Preliminary evidence suggests bilberry leaf might lower blood glucose. Theoretically, diabetes drugs might require dosing adjustment if bilberry leaf is used.

Toxicology

Extensive toxicological investigation has demonstrated that bilberry anthocyanoside extracts are devoid of toxic effects. Administration to rats, mice and rabbits of daily dosages of 600 mg per day produced no teratogenic effects. Daily doses in rats as high as 400 mg/kg produces no apparent side-effects, with excess levels quickly excreted through the urine and bile.

The LD50 of bilberry extract standardized to contain 36% anthocyanins was greater than the equivalent of 720 mg/kg anthocyanins in rats and mice. Oral administration of doses containing up to the equivalent of 180 mg/kg anthocyanins per day for 6 months produced no toxic, mutagenic or teratogenic effects.

Weak activity for bilberry extract was noted in the Ames mutagenicity test, likely due to quercitin.

Contraindications

None known.

Very high doses should be used cautiously in patients with hemorrhagic disorders and in those taking warfarin and antiplatelet drugs.