A healthy blend of polyphenols from Canadian wild blueberries and french grapes COGNITIVE HEALTH

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1 A healthy blend of polyphenols from Canadian wild blueberries and french grapes COGNITIVE HEALTH

2 Cerebelle TM : promoter of your brain health What is Cerebelle TM? Cerebelle TM is a standardized mixture of extracts obtained from Canadian wild blueberries and French grapes. Blueberries are a major source of proanthocyanidins (PACs) and phenolic acids (chlorogenic acid), while grapes are a rich sources of stilbenes and flavonols (catechins and epicatechins). Traditionally, products known to contain these molecules have been associated with the protection of cognitive functions. The proprietary process developed for the extraction of these molecules allows reaching concentrations of flavonols up to 29% (29% TF). The antioxidant capacity of Cerebelle TM has been measured at 21, in ORAC (μmols Trolox/g of dry weight). Cerebelle TM comes in powder form and is low in calories. 2 Cerebelle TM Content (% of total polyphenols) Flavonols/phenolic acids Resveratrol Anthocyanins Proanthocyanidins Epicatechins Catechins

3 Cerebelle TM : what for? Cerebelle TM is indicated in the prevention of the normal cognitive decline associated with aging (primary cognitive decline). The national institute on Aging (a division of the NIH) estimates that by 25, the number of people aged of 65+ will represent more than 16% of all individuals worldwide, for a total just under 1.5 billion. Data from recent studies have shown that the prevalence of mild cognitive impairment in the population of 7 to 75 years of age to be between 15 to 2%. Changes in life style (including increase consumption of polyphenols from fruits and vegetables) have now been associated, along with exercising and good control of high blood pressure, with a lower risk of developing dementia in elderlies. Cerebelle TM is providing in a daily dose the equivalent of polyphenols contained in 15 grams of fresh fruit. Cerebelle TM : bioavailability and excretion. The bioavailability of the different components in Cerebelle TM has been studied both in animal and human with consistent results showing that the combination of wild blueberry and grape extract is increasing the bioavailability of chlorogenic acid (a compound unique to wild blueberry) which has been demonstrated in the in vitro human cell line study to prevent oxidation of neuronal cells. PLASMA CONCENTRATION Metabolite Control Blueberry Grape Cerebelle TM Gallic acid ND 189,2 ± 31, ± 1372, 1835, ± 2464, Chlorogenic acid ND 362, ± 87,2 ND 1962,1 ± 783,9 Resveratrol ND ND 44,6 ± 17,3 119,7 ± 45,3 Catechin ND ND 967,7 ± 356,9 821,3 ± 227,1 Epicatechin ND ND 274,7 ± 549,9 37,7 ± 158,5 Université Laval, 215 Catechin Epicatechin PACs Dimers B The human Cerebelle TM clinical study was also successful to demonstrate a significant higher excretion rate of epicatechins, catechins and their metabolites, and a lower secretion of chlorogenic acid, confirming the positive interaction of both extract in changing absorption profile of phenolic compounds. nm Cerebelle TM V1 V2 nm Cerebelle TM V1 V2 nm Cerebelle TM V1 V2 Polyphenols that fight aging Aging Recent research suggests that dietary supplementation with wild blueberry extract is effective in reversing age-related brain deficits and behaviorial function (Shukitt-Hale. 28). Furthermore, epidemiologic evidence has implicated that dietary polyphenols from grape may protect against cognitive deterioration in aging. (Pasinetti, 212). In the brain, aging is generally associated with cumulative oxidative and inflammatory insults, as defense mechanisms weaken. A key to reduce the incidence of age-related cognitive deficits might thus be to act on the neuronal environment to prevent or dim neuroinflammation and oxidative stressinduced neurotoxicity (Vauzour, 21). Cerebelle TM has just the right polyphenol profile to support such neuroprotective, antioxidant, and anti-inflammatory activities. POLYPHENOLS Neuroinflammation Neuronal Dysfunction POLYPHENOLS POLYPHENOLS Neurotoxicity Cognitive impairment Alzheimer s disease Parkinson s disease

4 Cerebelle TM : human clinical trial STUDY DESIGN: Cerebelle TM has been evaluated in a placebo-controlled, randomized, double-blind study, in collaboration with the Institute of Nutraceuticals and Functional Foods (INAF) at Laval University (Canada) and the National Institute for Agricultural Research (INRA) at the University of Bordeaux in France. The study investigated the effect of Cerebelle TM (2 x serving of 3 mg Cerebelle TM /day = 6 mg of Cerebelle TM or 175 mg of flavonols) on cognitive functions in a panel of 2 healthy adults, aged 6-7, over a period of 6 months. Logical, visual, and spatial memory performances were evaluated, as well as psychological aspects such as depression, fatigue, and quality of life, often altered with cognitive decline. Blood and urine samples were collected at the beginning and at the end of the study for biochemical analysis. (Paired Associated Learning test) in individual who has recorded at the entry of the study the worst score at the PAL test. Therefore, regular supplementation of Cerebelle TM should be largely beneficial to individuals already showing mild first signs of primary cognitive decline as measured by PAL test. 4 Separation of population by quartiles following their performances at the test prior the supplementation (V1): 1 (best results) / 4 (worst results) Cerebelle TM has demonstrated that it can helps visual memory and associated learning has assessed by the PAL test Moy. des cellules 9 8 1, Active 7 1, 6 2, Active 2, 5 3, Active 4 3, 4, Active 3 4, 2 1 PAL tot errors adj V1 PAL tot errors adj V2 Moy. des cellules pour PAL tot errors adj V2-V Cerebelle TM treatment improved the performances of volunteers with the low results prior the supplementation (quartile 4) p=194 Active 1. Cerebelle TM has also demonstrated that it can help verbal memory and new learning (encoding new information and subsequently retrieving such verbal information) in individuals who have the low VRM score at the entry of the trial, supporting the benefit of regular supplementation of Cerebelle TM to improve short memory and abilities to retrieve such information. VRM Free recall Total correct Immediate recall p=286 Active Moy. des cellules pour PAL tot errors adj V2-V p=412 Cerebelle TM treatment improved the performances of volunteers with bad results prior the supplementation (quartiles 3 & 4) p= Active

5 How does Cerebelle TM works: The positive effect of Cerebelle TM supplementation on cognitive functions can be explained by a modulation in the expression of genes involved in neuronal plasticity. Indeed, the brain of mice on a Cerebelle TM enriched diet revealed increased of mrna levels of nerve growth factor (NGF) and Ca2+/calmodulin-dependent protein kinase (CamKII). NGF is expressed by neurons in the hippocampus and facilitates spatial memory through an action of cholinergic neurons (Conner, 29). CamKII is also expressed in the hippocampus. This protein kinase in involved in many signalling cascades related to learning and memory. Expression of NGF was not influenced by age. However. Cerebelle TM supplementation stimulated its production in both young and aged mice. CamKII expression was decreased in the brain of aged mice, an affect that could be reversed under Cerebelle TM diet. Such results suggest that Cerebelle TM supplementation may prevent or retard age-related cognitive decline, in a natural nutritional way. Modulation of gene expression Source: Bensalem et al, # # * * 1 1 Normalized ratio (%) Normalized ratio (%) Young NGF Aged Polyphenol Control Young CamKll Aged

6 In animal and clinical studies, it has been shown that when combined together, the extracts from wild blueberry and grape will increase the bioavailability of some key metabolites which are contributing to decrease systemic inflammation including inflammation at the brain cell levels. It is believed that catechins from grape extract are inhibiting or saturating the efflux transporters of the enterocytes on the side of the lumen of the GI tract letting the anthocyanes from wild blueberry and grape to enter more easily the blood stream. The blood concentration as measured by UPLC-MS/MS of four metabolites specific to wild blueberry were significantly more absorbed when combined with the grape extract. It is noteworthy to observe an increase of the excretion in the stool of the individuals on the Cerebelle TM group of catechins, epicatechins and their related metabolites. Blueberry extract Cerebelle TM 3.5 Chlorogenic acid 5 Quercetin glucuronide 6 Blood Enterocyte Lumen Apical intake transporters (SGLT, GLUT) Basolateral transporters (M RP1, 3, 5) Apical efflux transporters (PgP, MRP2, BCRP) Inhibition or saturation of efflux transporters Anthocyanins, flavors, phenolic acids from blueberry extract (μmol/l plasma) (μmol/l plasma) % B G N Petunidin 3 - glucoside +447% (μmol/l plasma) (μmol/l plasma) 6 +23% B G N Malvidin 3 - glucoside +369% Catechins from grape extract B G N B G N Who may benefit from Cerebelle TM supplementation? The aging population in general, whether healthy or with a genetic predisposition to develop accelerated neurodegeneration, may benefit from regular supplementation with Cerebelle TM. Younger adults who wish to preserve their cognitive functions may also profit from the regular consumption of Cerebelle TM in conjunction with a healthy life style and activities stimulating brain (like reading or memory games). Recommended dosage: Suggested dosage: 1 or 2 capsules of 3 mg of Cerebelle TM per day at breakfast time / Duration: as long as needed Stability data: Stability studies on the ingredient Cerebelle TM were perfomed by two independent laboratories. Results showed that the ingredient remained stable over time. TOTAL PHENOLS/CAPSULE, AS GALLIC ACID (FOLIN-CIOCALTEU) (UV) Time Point Result Theoretical level STABILITY DATA FOR THE CEREBELLE INGREDIENT T T6 Baseline 263 mg 2 6 months months Université Laval, Canada, 215 Total polyphenols Catéchine (LC-MS) 13,7 12,3 Épicatéchine (LC-MS) 9,8 8,6 OPC (FLUO) Anthocyanes,17,1 Resvératrol Polyphenols Biotech, France, 215

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8 April 218 credits : Fotolia - istock Sales European office: 7, Allée Ermengarde d Anjou ZAC Atalante Champeaux CS Rennes CEDEX FRANCE Phone : + 33 () Fax : + 33 () contact@diana-food.com This brochure concerns industry professionals. It only pertains to food ingredients not final food products. It is the responsibility of each manufacturer to verify the compliance of the final product s labeling and communication indicated on the finished foods to be delivered as such to the consumer with respect to the current local legislation. In Europe, this is based on regulation (EC) No 1924/26 on nutrition and health claims.