Grape seed extract

Synonym(s): oligomeric proanthocyanidins, OPC, Polyphenols, proanthocyanidins, resveratrol, grape seed extract, grape seeds

Nutrient group: plant extracts & active ingredients, Antioxidants, Hormonal substances

Sources and physiological effects

Dietary sources
Extracts from grape seeds are used as preventive and therapeutic components of dietary supplements or special dietary foods due to their high content of oligomeric proanthocyanidins (OPC).
Physiological effects
Antioxidant	Increase in antioxidative capacity Inhibition of lipid peroxidation Regeneration of vitamin C, vitamin E and L-glutathione
Inflammation	Inhibition of proinflammatory cytokines
Pain	Inhibition of cyclooxygenase (COX) 1 and 2
Immune system	Stimulation of the immune system
Cardiovascular	Vasodilative effect by increasing endothelial NO bioavailability
Cell growth	Control of cell cycle and inhibition of cell proliferation Induction of apoptosis Induction of tumor suppressor genes

Detailed information

Polyphenols from grapes

The group of polyphenols includes flavonoids, anthocyanins and oligomeric proanthocyanidins (OPC), which are widely used as bioactive plant substances. They have an extremely broad spectrum of action. In addition to their anticarcinogenic, antimicrobial, antiedematous, antiphlogistic and immunomodulating properties, they offer distinct, efficient protection against oxidation. They are superior to vitamins in their cytoprotective and antioxidative efficacy. The main indications include the prevention of cardiovascular diseases and treatment of atherosclerotic changes, tumor prophylaxis and therapeutic use for connective tissue weaknesses.

Plant-based active substances are the strongest antioxidants

The antioxidative capacity of plant extracts is attributed to various mechanisms. These include the ability to chelate with transition metals, the release of electrons from the phenolic hydroxyl group and the inhibition of prooxidative enzymes (1). Trans-Resveratrol is effective in both lipophilic and hydrophilic environments. At the molecular level, it shows a better mobility of its three hydrogen atoms than other antioxidants, resulting in an improved transfer of electrons to the radical molecules (2).
Due to their pharmacologically and therapeutically effective properties as bioreductors and their high bioavailability, grape, grape seed extracts, and resveratrol are suitable phytotherapeutics for the prevention and treatment of oxidative stress in various target organs and tissues (3).

Properties of polyphenols - French Paradox

It has been established that the various constituents of wine and their orthomolecular properties are responsible for the "French Paradox". This refers to the phenomenon that, despite a high intake of cholesterol and saturated fats, the French population has a much lower mortality from cardiovascular diseases than comparable nations. Based on epidemiological studies, increased red wine consumption was identified as the cause of increased polyphenol intake. The red wine polyphenols improve vascular functions primarily through NO-mediated mechanisms, prevent oxidative processes that drive vascular damage and prevent atherosclerosis-promoting events already in an early phase. Meta-analyses show a significant negative association between moderate wine consumption and cardiovascular risk (4).
Grape polyphenols are also characterized by vasodilatory properties controlled by the endothelial function (5) and increase the oxidation resistance of LDL cholesterol to free radicals (6). In hypercholesterolemia, both statins and resveratrol can exert cardioprotective effects through NO-mediated mechanisms. In a clinical study, it was shown that a combination of statins with resveratrol was better at reducing atherosclerotic processes and had a higher protective effect on heart muscle cells than statins alone (7). In addition, neovascularization processes are effectively promoted by this combination, resulting in positive long-term effects (8).

Immunomodulating and neuroprotective effects

Numerous studies deal with the immunomodulatory effects of OPCs. OPCs demonstrated immune-enhancing activities by increasing lymphocyte proliferation and cell toxicity to cancer cells. OPC-rich supplements were also found to stimulate the immune system via interleukin-2 secretion (9).
Recent research has focused on the effect of OPC on age-related cognitive deficits. The neuroprotective effects of OPC demonstrated in animal experiments are explained by protein-specific mechanisms (10). The ability of resveratrol to cross the blood-brain barrier and stimulate the detoxification performance of enzymes in the brain is highlighted, which at least partly explains the neuroprotective effect (11).
In diabetic neuropathies, treatment with resveratrol in animal experiments showed a significant improvement in the speed of nerve conduction and the blood flow to the nerve tissue. Resveratrol is believed to have a therapeutic potential in diabetic neuropathies based primarily on its recognized antioxidant properties (12).

Resveratrol activates sirtuins

Resveratrol or pterostilbene from grapes, curcumin from turmeric and sulforaphane or glucoraphanin from broccoli have a direct effect on the sirtuin system and stimulate the production of antioxidant and neuroprotective enzymes as well as the production of sirtuins, which in turn stimulate the production of antioxidant and neuroprotective enzymes. This enhances their antioxidant and neuroprotective effect (19)(20)

Venous insufficiency and the use of OPC as anti-edemics

Due to their antiedematous, antiphlogistic and antioxidative properties, OPCs are increasingly used for the therapeutic treatment of connective tissue weaknesses and as a concomitant therapy in the initial phases of venous diseases. They normalize disturbed vascular permeability, bring the overstretched veins back to their normal diameter and help to reduce fluid accumulations in the tissue. They can also protect the fine vessel walls and the surrounding connective tissue from age-related oxidative processes. In one study, at a daily dose of 100 mg OPC, over 80% of patients showed significant improvements after 10 days (13). Studies have shown that even during the first weeks of treatment there is a significant improvement in the symptoms of chronic venous insufficiency. Both pain and itching as well as swelling in the ankle area can be reduced (13).

Grape seed OPCs are potent antioxidants for the skin

Oligomeric proanthocyanidins from grape seeds have also proven to be relevant for the protection of skin structures. In addition to their immunomodulating and anti-inflammatory properties, these "phytochemicals" also show strong antioxidant and anticarcinogenic effects (14). In several studies, the protective effect of selected substances on UV-induced skin carcinogenesis was also demonstrated (15).

Tumor prophylaxis and increased efficiency in radiation therapy

OPC and resveratrol have a high preventive potential in the development of tumor cells, which can be demonstrated experimentally in all 3 stages of carcinogenesis. Results from in vitro and in vivo studies show that resveratrol can effectively block tumor initiation, promotion and progression in the process of carcinogenesis. Some of the underlying biochemical mechanisms have also been identified (17). Scientific data also suggests that resveratrol may increase the susceptibility of tumor cells to radiation. Since the use of radiation therapy is limited by the strong toxicity to healthy cells, another possible field of application for resveratrol is indicated here (18).

Cutting-edge technology for obtaining an unadulterated polyphenol raw material
Grape seed extract and total grape extract are produced from red and white grapes in a complex extraction, concentration and purification process. To obtain 1 kg of total grape extract 4166 kg of grapes are needed, for 1 kg of grape seed extract even 8333 kg. The extraction is carried out without the use of organic solvents, the subsequent gentle drying in a special spray drying process takes place without carrier material, so that a concentrated and unadulterated raw material is available. In order to guarantee the pharmacological properties of the extracts, a 3-fold (grape seed extract) or 5-fold (total grape extract) standardisation is carried out on the polyphenol components contained.

The ORAC value as a measure of antioxidative capacity

ORAC (Oxygen Radical Absorbance Capacity) is a method for measuring the antioxidant potential of substances. This allows the antioxidant protection exerted by plant extracts or orthomolecular micronutrients against free radicals to be recorded and compared.
Trolox, a vitamin E replica, is used as the standard antioxidant or reference antioxidant. Thus, the unit of measurement for ORAC is the so-called trolox equivalent (TE). The ORAC value is expressed in µmol trolox equivalent per unit weight. In order for the ORAC values of substances to be compared, the measurement method must also be specified. Today, ORAC-FL is generally used, whereas earlier studies used ORAC-PE (1). In order to build up a sufficient antioxidative potential in the body, the UDSA (Human Nutrition Research Center on Aging) recommends a daily intake of 4000 - 5000 ORAC units (µmol TE) per day. This corresponds to about 7 portions of fruit and vegetables.

Reference values

Parameters	substrate	reference value	Description
Pyridoxal-5‘-phosphate (P5P)	Serum	3.3 - 9.2 µg/l	Fasting (12 h). Protect from light during storage and transport. P5P is the most abundant vitamin B₆ metabolite, therefore only P5P is usually determined.
	Whole blood	11.3 - 22.5 µg/l
Aspartate aminotransferase activation coefficient (AST)	Red cell hemolysate	> 2.0	Enzymatic UV test to determine the activity of this enzyme without or with the addition of PLP. This is used to determine an activation coefficient.
Interpretation
Low values: P5P		Indication of vitamin B₆ deficiency
High values: AST activation coefficient		Indication of vitamin B₆ deficiency

Nutrigenetics
Characteristic gene sites and their effects on vitamin requirements

Gene	rsNumber	risk SNP	Description	Recommended nutrients
MTHFR	rs1801133	T	The transmethylation by this enzyme is reduced, the need for folic acid and vitamin B6 is increased This SNP is associated with increased homocysteine levels. Vitamin B2 (riboflavin) can increase the activity of the MTHFR enzyme, therefore an increased intake is recommended. Vitamin B6 and folic acid should always be taken together with vitamin B12 (19)(20)(21)(22).	B₂, B₆, B₁₂ and folic acid

Indications

Effect	Indication	Dos
Physiological effects at a low intake	To improve antioxidant status and to treat oxidative stress	200 – 1200 mg/d
	Preventive and concomitant therapeutic to improve the antioxidative status in cardiovascular diseases, reduces arteriosclerotic changes and LDL values as well as to support statin therapy	200 – 1200 mg/d
	For prevention and treatment of venous disorders of the legs, haemorrhoids	200 – 1200 mg/d
	Complementary therapy for connective tissue weakness and couperose	200 – 1200 mg/d
	For tumor prophylaxis and to increase of the effectiveness of radiation therapies	200 – 1200 mg/d
	Preventive and concomitant therapeutic for diabetic neuropathies	200 – 1200 mg/d

Administration

General mode of administration
When	Grape seed extract can be taken with or between meals.
Side effects
No side effects are known to date.
Contraindications
No contraindications are known to date.

Interactions

Drug interactions (according to Gröber)
None	No relevant interactions are known to date.
Nutrient interactions
Micronutrients	Polyphenols inhibit the absorption of iron when taken at the same time.
Glucosamine	In combination with OPCs (Pycnogenol) glucosamine shows improved chondroprotective effects.

References

1) Hahn, A. et al. Ernährung: Physiologische Grundlagen, Prävention, Therapie, 3. neu bearbeitete und erweiterte Auflage. Stuttgart: Wissenschaftliche Verlagsgesellschaft Stuttgart, 2016.
2) Caruso, F. et al. 2004. Structural basis for antioxidant activity of trans-resveratrol: ab initio calculations and crystal and molecular structure. J Agric Food Chem. 52(24):7279-85.
3) Bagchi, D., et al. 2002. Cellular protection with proanthocyanidins derived from grape seeds. Ann N Y Acad Sci. 957:260-70.
4) De Gaetano, G., Cerletti, C. 2001. European project: FAIR CT 97 3261: Wine and cardiovascular disease. Nutr Metab Cardiovasc Dis. 11(4S):47-50.
5) Lekakis, J. et al. 2005. Polyphenolic compounds from red grapes acutely improve endothelial function in patients with coronary heart disease. Eur J Cardiovasc Prev Rehabil. 12(6):596-600.
6) Bagchi, D. et al. 2003. Molecular mechanism of cardioprotection by a novel grape seed proanthocyanidin extract. Mutat Res. 523-524:87-97.
7) Penumathsa, S. V. et al. 2006. Statin and resveratrol in combination induces cardioprotection against myocardial infarction in hypercholesterolemic rat. J Mol Cell Cardiol. 42(3):508-516. doi: 10.1016/j.yjmcc.2006.10.018.
8) Yoshida, Y. et al. 2007. Resveratrol ameliorates experimental autoimmune myocarditis. Circ J. 71(3):397-404. doi: 10.1253/circj.71.397.
9) Zhang, X. Y. et al. 2005. Proanthocyanidin from grape seeds potentiates anti-tumor activity of doxorubicin via immunomodulatory mechanism. Int Immunopharmacol. 5(7-8):1247-57.
10) Kim, H. et al. 2006. Proteomics analysis of the actions of grape seed extract in rat brain: technological and biological implications for the study of the actions of psychoactive compounds. Life Sci. 78(18):2060-5. doi: 10.1016/j.lfs.2005.12.008.
11) Mokni, M. et al. 2007. Effect of resveratrol on antioxidant enzyme activites in the brain of healthy rat. Neurochem Res. 32(6):981-987. doi: 10.1007/s11064-006-9255-z.
12) Kumar, A. et al. 2007. Effects of resveratrol on nerve functions, oxidative stress and DNA fragmentation in experimental diabetic neuropathy. Life Sci. 80(13):1236-44. doi: 10.1016/j.lfs.2006.12.036.
13) Costantini, A. et al. 1999. Clinical and capillaroscopic evaluation of chronic uncomplicated venous insufficiency with procyanidins extracted from vitis vinifera. Minerva Cardioangiol. 47(1-2):39-46.
14) Watzl, B., Leitzmann, C. Bioaktive Substanzen in Lebensmitteln, 1. Auflage. Stuttgart: Hippokrates Verlag, 1999.
15) Baliga, M. S., Katiyar, S. K. 2006. Chemoprevention of photocarcinogenesis by selected dietary botanicals. Photochem Photobiol Sci. 5:243-53. doi: 10.1039/B505311K.
16) Han, B. et al. 2003. Proanthocyanidin: a natural crosslinking reagent for stabilizing collagen matrices. J Biomed Mater Res A. 65(1):118-24.
17 Li, Y. et al. 2006. Resveratrol- induced cell inhibition of growth and apoptosis in MCF7 human breast cancer cells are associated with modulation of phosphorylated Akt and caspase-9. Appl Biochem Biotechnol. 135(3):181-92. doi: 10.1385/ABAB:135:3:181.
18) Scarlatti, F. et al. 2007. Resveratrol sensitization of DU145 prostate cancer cells to ionizing radiation is associated to ceramide increase. Canc Lett. 253(1):124-130. doi: 10.1016/j.canlet.2007.01.014.

Referenzen Interaktionen
Stargrove, M. B. et al. Herb, Nutrient and Drug Interactions: Clinical Implications and Therapeutic Strategies, 1. Auflage. St. Louis, Missouri: Elsevier Health Sciences, 2008.
Gröber, U. Mikronährstoffe: Metabolic Tuning –Prävention –Therapie, 3. Auflage. Stuttgart: WVG Wissenschaftliche Verlagsgesellschaft Stuttgart, 2011.
Gröber, U. Arzneimittel und Mikronährstoffe: Medikationsorientierte Supplementierung, 3. aktualisierte und erweiterte Auflage. Stuttgart: WVG Wissenschaftliche Verlagsgesellschaft Stuttgart, 2014.