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Modulatory effect of coffee fruit extract on plasma levels of brain-derived neurotrophic factor in healthy subjects

Published online by Cambridge University Press:  14 January 2013

Tania Reyes-Izquierdo*
Applied BioClinical, Inc., 16259 Laguna Canyon Road, Irvine, CA92618, USA
Boris Nemzer
FutureCeuticals, Inc., 2692 North State Route 1-17, Momence, IL60954, USA
Cynthia Shu
Applied BioClinical, Inc., 16259 Laguna Canyon Road, Irvine, CA92618, USA
Lan Huynh
Applied BioClinical, Inc., 16259 Laguna Canyon Road, Irvine, CA92618, USA
Ruby Argumedo
Applied BioClinical, Inc., 16259 Laguna Canyon Road, Irvine, CA92618, USA
Robert Keller
NutraClinical, Inc., 5755 Oberlin Drive, Suite 301, San Diego, CA92121, USA
Zb Pietrzkowski
Applied BioClinical, Inc., 16259 Laguna Canyon Road, Irvine, CA92618, USA
*Corresponding author: T. Reyes-Izquierdo, fax +1 949 502 4987, email
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The present single-dose study was performed to assess the effect of whole coffee fruit concentrate powder (WCFC), green coffee caffeine powder (N677), grape seed extract powder (N31) and green coffee bean extract powder (N625) on blood levels of brain-derived neurotrophic factor (BDNF). Randomly assorted groups of fasted subjects consumed a single, 100 mg dose of each material. Plasma samples were collected at time zero (T0) and at 30 min intervals afterwards, up to 120 min. A total of two control groups were included: subjects treated with silica dioxide (as placebo) or with no treatment. The collected data revealed that treatments with N31 and N677 increased levels of plasma BDNF by about 31 % under these experimental conditions, whereas treatment with WCFC increased it by 143 % (n 10), compared with baseline. These results indicate that WCFC could be used for modulation of BDNF-dependent health conditions. However, larger clinical studies are needed to support this possibility.

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Copyright © The Authors 2012 

Brain-derived neurotrophic factor (BDNF) is a member of the nerve growth factor-related family(Reference Fujinami, Ohta and Obayashi1) and is a homodimeric protein that has been highly conserved in structure and function during evolution(Reference Jones and Reichardt2, Reference Maisonpierre, Le Beau and Espinosa3). BDNF is a secreted protein that, in human subjects, is encoded by the BDNF gene(Reference Maisonpierre, Le Beau and Espinosa3). It is involved in development, maintenance and function of the central nervous system(Reference Tessarollo4, Reference Yamamoto, Sobue and Yamamoto5). BDNF is found in a wide range of tissues(Reference Maisonpierre, Le Beau and Espinosa3) and it can be self-regulated(Reference Cunha, Angelucci and D'Antoni6, Reference Cunha, Brambilla and Thomas7). BDNF has several documented short- and long-term functional roles. It is now well-known that BDNF serves as a target-derived survival and differentiation factor for neuronal sub-populations in prenatal stages(Reference Grothe and Unsicker8Reference Snider10). Likewise, BDNF promotes long-term potentiation by potentiating excitatory neurotransmitter activity in the hippocampus(Reference Boulanger and Poo11) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor insertion post-synaptically(Reference Li and Keifer12). These actions, along with BDNF's ability to stabilise dendritic spines(Reference Tanaka, Horiike and Matsuzaki13), underlie the molecule's important role in learning, memory and behaviour(Reference Cunha, Brambilla and Thomas7). In addition, BDNF levels increase in response to certain forms of injury, such as ischaemic–hypoxic(Reference Han and Holtzman14) and infectious insults(Reference Bifrare, Kummer and Joss15), presumably by blocking apoptosis. Various studies have shown a link between BDNF and certain health conditions, such as depression(Reference Brunoni, Lopes and Fregni16, Reference Dwivedi17), obsessive–compulsive disorder(Reference Maina, Rosso and Zanardini18), Alzheimer's disease(Reference Zuccato and Cattaneo19), dementia(Reference Arancio and Chao20) and Parkinson's disease(Reference Fumagalli, Racagni and Riva21, Reference Chun, Son and Son22).

Despite its name, BDNF is found in a variety of tissues and cell types, not just in the brain. It is also expressed in cardiovascular, immune, reproductive and endocrine tissues(Reference Tessarollo4, Reference Yamamoto, Sobue and Yamamoto5, Reference Seifer, Feng and Shelden23). Intact BDNF readily crosses the blood–brain barrier via a high-capacity transporter system(Reference Pan, Banks and Fasold24). Interestingly, exercise has been shown to increase the expression of BDNF in human subjects(Reference Kramer, Colcombe and McAuley25Reference Kramer, Hahn and Cohen27) and a similar effect was observed after caffeine application in vitro (Reference Connolly and Tamy28) and in vivo (Reference Costa, Botton and Mioranzza29). Caffeine has been recently proposed as a potential candidate for maintaining physiological levels of BDNF, as it is capable of positively affecting cognition(Reference Costa, Botton and Mioranzza29, Reference Alhaider, Aleisa and Tran30). In the present study, we tested polyphenol-rich natural products containing different amount of caffeine to see if a single dose could lead to an increase in plasma levels of BDNF. Three natural products containing varying amounts of caffeine were selected for the present pilot study: green coffee caffeine (N677), green coffee bean extract (N625) and whole coffee fruit concentrate powder (WCFC)(Reference Heimbach, Marone and Hunter31). A grape seed extract (N31) containing high levels of polyphenols, but not caffeine(Reference Yashin, Nemzer and Ryzhnev32), was also tested.

Materials and methods


Extract powders tested in the present study were provided by FutureCeuticals, Inc. WCFC is a patented extract of whole coffee fruit (coffee berries) from Coffea arabica. Chemical composition and polyphenol profiles of each tested extract appear in Table 1. Dulbecco's PBS and water were purchased from Sigma Chemical Company. Protein low binding microtubes were obtained from Eppendorf and RC DC Protein Assay Kit II was purchased from Bio-Rad. Human BDNF Quantikine ELISA kits were from R&D Systems. Heparin blood collection tubes were obtained from Ram Scientific, Inc. and lancets were purchased from Medlance®. Silica oxide used as placebo was also purchased from Sigma Chemical Company.

Table 1 Amount of caffeine, polyphenols and procyanidins in extracts tested in the present study

WCFC, whole coffee fruit concentrate powder; N677, green coffee caffeine powder; N625, green coffee bean extract powder; N31, grape seed extract powder; ND, not determined; ORAC, oxygen radical absorbance capacity; TE, Trolox™ equivalents; HORAC, hydroxyl oxygen radical absorbance capacity; SORAC, superoxide radical absorbance capacity; NORAC, peroxynitrite radical absorbance capacity; SOAC, singlet oxygen radical absorbance capacity.

Study description

The present study was conducted according to the guidelines laid down in the Declaration of Helsinki, and all procedures involving human subjects/patients were approved by the Institutional Review Board at Vita Clinical S.A. Avenida Circunvalacion Norte #135, Guadalajara, JAL, Mexico 44 270 (study protocol no. 12-06 ABC-BDNF). The present pilot acute clinical study was performed on healthy fasted subjects treated once with a single dose of tested material, placebo (silica oxide) or vehicle only (water). All study subjects were generally healthy, non-smokers and did not use any type of medication or supplement for a period of 15 d prior to the start of the study. The inclusion criteria required participants to be between the ages of 18 and 55 years and have a BMI between 18·0 and 25·0 kg/m2(Reference Borecki, Higgins and Schreiner33). At the time of the study, participants were free of rhinitis, influenza and other symptoms of upper respiratory infection. To minimise confounding effects, all subjects remained in the testing facility during experimentation to avoid the possibility of blood BDNF increase due to physical activity and exercise(Reference Zolodz, Majerczak and Grandys34). In addition, all subjects were tested during the same time of day to minimise any differences in blood BDNF due to diurnal effect(Reference Piccini, Marazziti and Del Debbio35). Participants were excluded if they had diabetes mellitus, a known allergy to any of the test ingredients or were using any anti-inflammatory, analgesic, anti-allergy, anti-depressant medication or multivitamins. Participants received oral and written information about the experimental procedures before giving their written consent.

For the present study, twenty-five(Reference Kramer, Colcombe and McAuley25) subjects were randomly divided into groups of five to receive one of the five treatments: N677, N625, N31, WCFC or placebo (silica oxide). In follow-up studies performed under the same experimental conditions, five participants received WCFC, chlorogenic acid or water as vehicle (no treatment group). In all cases, subjects fasted for 12 h prior to the first blood collection. Other than consuming one of the study materials or placebo, patients had no intake per os during the study period. Blood was collected at baseline (T 0) and subsequent samples were collected at every 30 min (T 30, T 60, T 90 and T 120) after the treatment.

Brain-derived neurotrophic factor detection and quantification

For the isolation of plasma, 100 μl finger blood were collected by finger puncture and placed in Safe-T-Fill® Capillary blood collection tubes (Ram Scientific, Inc.) and centrifuged at 1000 g for 10 min. Blood was transferred to protein low binding tubes and kept at − 80°C until use. BDNF was measured using a quantitative sandwich ELISA immunoassay (R&D Systems) following the instructions provided in the kit, using the buffers and calibrators specific for plasma. Final reactions were measured using a spectrophotometer (Molecular Devices) at 450 and 540 nm wavelengths, and final concentrations were calculated from a standard curve.

Chemical analyses

Chlorogenic acid, procyanidins, flavanols and flavonols of WCFC, N625 and N31 were characterised by LC–MS(n) and quantified by UV absorbance(Reference Mullen, Nemzer and Ou36). Total polyphenol content was determined by spectrophotometry according to the Folin–Ciocalteu method(37), and was calibrated against gallic acid standard (Sigma-Aldrich). Results were expressed as grams of gallic acid equivalents.

The caffeine and trigonelline contents were characterised by HPLC Agilent 1100 (Agilent Technologies) equipped with a diode array detector and quantified by UV absorbance (W Mullen, B Nemzer, M Clifford, et al., unpublished results). Antioxidant capacities of coffee fruit extract, coffee bean extract and N31 were characterised by the ability of the samples to scavenge peroxyl radicals (oxygen radical absorbance capacity), hydroxyl radicals (hydroxyl oxygen radical absorbance capacity), peroxynitrite (peroxynitrite radical absorbance capacity), superoxide anions (superoxide radical absorbance capacity) and singlet oxygen (singlet oxygen radical absorbance capacity)(Reference Huang, Ou and Hampsch-Woodill39Reference Zhang, Huang and Kondo41).

Statistical analysis

BDNF levels were compared with a reference standard curve and each subject was normalised to their own value measured at time zero (T 0). Peak levels of plasma BDNF for each patient were used for comparisons. Results were pooled and standard error of the mean was used for each separate analysis. Plasma BDNF levels at 60 min after treatment were compared with baseline using a two-tail, independent Student's t test. Power analyses were run using G*Power Data Analysis (Heinrich-Heine-University Düsseldorf). Statistical power was run for the whole group and it was also calculated per-pair power for individual comparison. Descriptive analysis was run in GraphPad to derive the mean and standard deviation for each group.

Results and discussion

Four polyphenol-rich fruit extracts were tested in healthy subjects. Three of the extracts contained caffeine in varying amounts (WCFC: 0·7 % caffeine; N677: 72·8 % caffeine; and N625: 2 % caffeine) and one extract was caffeine free (N31) (see Table 1). Of the substances tested, WCFC increased BDNF plasma levels (Fig. 1) in patients by an average of 137 % with respect to baseline (range 65–222 %; P= 0·001 v. placebo). N677 showed an increase of 42 %, but was not statistically significant (P= 0·49). N625 did not cause a significant increase in BDNF. N31 increased BDNF levels in plasma by 30 % with respect to baseline, though not significantly (P= 0·65).

Fig. 1 Blood levels of brain-derived neurotrophic factor (BDNF) collected from subjects treated with whole coffee fruit concentrate powder (WCFC), green coffee bean extract powder (N625), green coffee caffeine powder (N677), grape seed extract powder (N31) and placebo (silica). Data represent average percentage difference from administration (T 0). * Mean value was significantly different compared with placebo by Student's t test (P< 0·05).

It is important to note that a power analysis of the entire sample indicated that forty subjects would be required to reach a power of 80 %. Our sample size was twenty-five, therefore one must interpret the lack of BDNF effect of N677, N625 and N31 with caution. Larger groups are required to make definitive conclusions for these treatments. However, the result of this power analysis does not diminish the statistical significance of WCFC on plasma BDNF levels. Indeed, a separate per-pair power analysis of WCFC and placebo showed a sample size of ten to have a greater than 99 % power.

Quite unexpectedly, treatment with placebo (silica dioxide) resulted in a 34 % reduction in BDNF blood levels (P= 0·09). Silica oxide was used as placebo, as it is generally considered to be an inert material. It has been previously reported that stress can decrease plasma levels of BDNF in some human and animal models(Reference Elzinga, Molendijk and Oude Voshaar42Reference Advani, Koek and Hensler44). However, the reduction of plasma BDNF due to the intake of silica/placebo has not been reported. Consequently, a second experiment was performed to verify the reproducibility of the effect of WCFC on BDNF and to test the effect of extended fasting (untreated control) on the baseline level of BDNF in blood.

A total of five additional healthy subjects who met the same inclusion criteria were treated with 100 mg WCFC. As before, all groups fasted for 12 h prior to testing, but the control group did not receive any treatment besides water as vehicle (200 ml) as it was used for treatment with WCFC. As shown in Fig. 2, BDNF plasma levels were increased in subjects treated with 100 mg of WCFC (148 % increase; P= 0·002). However, blood BDNF level in the untreated group was not statistically changed (15 % increase by average).

Fig. 2 Blood levels of brain-derived neurotrophic factor (BDNF) measured in non-treated subjects (placebo), subjects receiving 50 mg of chlorogenic acid or 100 mg whole coffee fruit concentrate powder (WCFC). Data are presented as the average percentage difference compared with baseline (T 0). * Mean value was significantly different compared with placebo by Student's t test (P< 0·05).

Pooling all ten subjects from the two studies, treatment with 100 mg of WCFC caused a 143 % increase in BDNF plasma levels. The stimulatory effect of caffeine on BDNF has been previously observed(Reference Costa, Botton and Mioranzza29, Reference Alhaider, Aleisa and Tran30, Reference Capiotti, Menezes and Nazario45, Reference Bairam, Kinkead and Lajeunesse46). However, as presented in Fig. 1, single-dose treatment with caffeine-containing extracts resulted in an increased level of plasma BDNF in a caffeine concentration-independent manner. As shown in Table 1, N677 is mostly comprised of caffeine (72·8 % by weight), yet caused only modest increases in plasma BDNF levels. The most profound increases in plasma BDNF were observed after treatment with WCFC, although this extract contains only 0·7 % caffeine by weight.

Previous reports have shown that procyanidins extracted from grape seeds are capable of stimulating neurotrophic factors in aged rats(Reference Xu, Rong and Xie47). These compounds have also been implicated in the regulation of metabolic disorders(Reference Fraga and Oteiza48, Reference Terra, Pallares and Ardevol49) that are BDNF dependent. The N31 used in the present study had relatively high polyphenol levels compared with the coffee fruit, coffee caffeine and coffee seed extracts, yet failed to significantly increase BDNF in blood.

This result suggests that the stimulatory effect of WCFC on the blood level of BDNF is not associated with the amount of polyphenols or caffeine per dose. Rather, the effect may be related to either the amount of procyanidins or to the unique coffee polyphenol profile of the WCFC material. According to the present analyses, WCFC shows a significant amount of procyanidins in comparison to N31, N625 and N677 (Table 1), suggesting that acute treatment with procyanidin-rich whole coffee fruit extracts (and possibly other procyanidin-rich extracts), may increase blood levels of BDNF in human subjects. Future work could include testing other procyanidin-rich extracts for their ability to raise plasma BDNF in order to confirm this hypothesis.

The amount of trigonelline also varied in each material tested (Table 1). As presented, WCFC and N625 contain the highest amount of this compound; however, the effect of WCFC on plasma BDNF is superior to the effect of N625 under the same experimental conditions, suggesting that this is not the primary agent responsible for increased BDNF levels in blood.

As WCFC contains high amounts of chlorogenic acid, it was hypothesised that this specific polyphenolic acid may cause an increase in blood level of BDNF. Consequently, we administered 50 mg of chlorogenic acid as a single dose to five healthy subjects. As presented in Fig. 2, chlorogenic acid did not increase blood level of BDNF in a statistically significant manner (P= 0·89), suggesting that this substance is not responsible for the ability of WCFC to increase BDNF.

The compounds tested in the present study had different concentrations of caffeine and polyphenols (Table 1). It is important to note that the present results show the percentage of caffeine within each tested compound, rather than an absolute mass of caffeine. Nevertheless, the present work suggests that procyanidins may have the ability to increase plasma BDNF levels and, perhaps, to a larger extent than caffeine itself. This is particularly interesting considering that recent research show that procyanidin oligomers play a role in neuroprotection from excitotoxic injury(Reference Narita, Hisamoto and Okuda50).

BDNF-dependent telomerase activity has been shown to promote neuron survival in developing hippocampal neurons(Reference Fu, Lu and Mattson51). Increased BDNF expression and telomerase activity after brain injury suggest that telomerase may play a role in BDNF-mediated neuroprotection. Furthermore, BDNF has been shown to up-regulate telomerase expression and activity in spinal motor neurons(52). These neurons, treated with BDNF, are more resistant to ex-cytotoxic injury, presumably from increased cellular resistance to apoptosis. It is interesting to speculate that WCFC possibly may also exert an anti-apoptotic effect through telomerase by increased BDNF activity.

WCFC was tested under experimental conditions reducing impact of possible confounding effects; for example, non-smokers were not included in the present study, since nicotine is known to increase blood levels of BDNF(Reference Wang, Liao and Yuan53). All subjects remained in the clinical site during the duration of the study to avoid any shifts in blood level of BDNF due to exercise and physical activity(Reference Zolodz, Majerczak and Grandys34). Finally, the present clinical study was performed in the morning starting at 08.00 hours, as it was reported that blood levels of BDNF are increased due to diurnal effect(Reference Piccini, Marazziti and Del Debbio35).

In summary, WCFC increased the blood level of BDNF during first 60 min after treatment with a dose of 100 mg. In order to confirm the results of the present pilot study, further clinical testing in a larger group is required.


The present study was funded by Futureceuticals, Inc. T. R.-I. conducted the experimental work, analysed the data and led the manuscript writing. C. S., L. H. and R. A. performed serum tests and helped in the data analysis. R. K. organised and helped execute clinical protocol of the study. B. N. designed and conducted all the chemical analysis. Z. P. designed and directed the study. We would like to thank Michael Sapko for his help in editing the manuscript. All authors declare that they have no conflicts of interest.


1Fujinami, A, Ohta, K, Obayashi, H, et al. (2008) Serum brain-derived neurotrophic factor in patients with type 2 diabetes mellitus: relationship to glucose metabolism and biomarkers of insulin resistance. Clin Biochem 41, 812817.Google Scholar
2Jones, KR & Reichardt, LF (1990) Molecular cloning of a human gene that is a member of the nerve growth factor family. Proc Natl Acad Sci U S A 87, 80608064.Google Scholar
3Maisonpierre, PC, Le Beau, MM, Espinosa, R III, et al. (1991) Human and rat brain-derived neurotrophic factor and neurotrophin-3: gene structures, distributions, and chromosomal localizations. Genomics 10, 558568.CrossRefGoogle ScholarPubMed
4Tessarollo, L (1998) Pleiotropic functions of neurotrophins in development. Cytokine Growth Factor Rev 9, 125137.Google Scholar
5Yamamoto, M, Sobue, G, Yamamoto, K, et al. (1996) Expression of mRNAs for neurotrophic factors (NGF, BDNF, NT-3, and GDNF) and their receptors (p75NGFR, trkA, trkB, and trkC) in the adult human peripheral nervous system and nonneural tissues. Neurochem Res 21, 929938.CrossRefGoogle ScholarPubMed
6Cunha, C, Angelucci, A, D'Antoni, A, et al. (2009) Brain-derived neurotrophic factor (BDNF) overexpression in the forebrain results in learning and memory impairments. Neurobiol Dis 33, 358368.Google Scholar
7Cunha, C, Brambilla, R & Thomas, KL (2010) A simple role for BDNF in learning and memory? Front Mol Neurosci 3, 1.Google Scholar
8Grothe, C & Unsicker, K (1987) Neuron-enriched cultures of adult rat dorsal root ganglia: establishment, characterization, survival, and neuropeptide expression in response to trophic factors. J Neurosci Res 18, 539550.Google Scholar
9Kalcheim, C & Gendreau, M (1988) Brain-derived neurotrophic factor stimulates survival and neuronal differentiation in cultured avian neural crest. Brain Res 469, 7986.Google Scholar
10Snider, WD (1994) Functions of the neurotrophins during nervous system development: what the knockouts are teaching us. Cell 77, 627638.Google Scholar
11Boulanger, LM & Poo, MM (1999) Presynaptic depolarization facilitates neurotrophin-induced synaptic potentiation. Nat Neurosci 2, 346351.Google Scholar
12Li, W & Keifer, J (2008) Coordinate action of pre- and postsynaptic brain-derived neurotrophic factor is required for AMPAR trafficking and acquisition of in vitro classical conditioning. Neuroscience 155, 686697.Google Scholar
13Tanaka, J, Horiike, Y, Matsuzaki, M, et al. (2008) Protein synthesis and neurotrophin-dependent structural plasticity of single dendritic spines. Science (New York, NY) 319, 16831687.Google Scholar
14Han, BH & Holtzman, DM (2000) BDNF protects the neonatal brain from hypoxic–ischemic injury in vivo via the ERK pathway. J Neurosci 20, 57755781.Google Scholar
15Bifrare, Y-D, Kummer, J, Joss, P, et al. (2005) Brain-derived neurotrophic factor protects against multiple forms of brain injury in bacterial meningitis. J Infect Dis 191, 4045.CrossRefGoogle ScholarPubMed
16Brunoni, AR, Lopes, M & Fregni, F (2008) A systematic review and meta-analysis of clinical studies on major depression and BDNF levels: implications for the role of neuroplasticity in depression. Int J Neuropsychopharmacol 11, 11691180.CrossRefGoogle ScholarPubMed
17Dwivedi, Y (2009) Brain-derived neurotrophic factor: role in depression and suicide. Neuropsychiatr Dis Treat 5, 433449.CrossRefGoogle ScholarPubMed
18Maina, G, Rosso, G, Zanardini, R, et al. (2010) Serum levels of brain-derived neurotrophic factor in drug-naive obsessive-compulsive patients: a case–control study. J Affect Disord 122, 174178.Google Scholar
19Zuccato, C & Cattaneo, E (2009) Brain-derived neurotrophic factor in neurodegenerative diseases. Nat Rev Neurol 5, 311322.CrossRefGoogle ScholarPubMed
20Arancio, O & Chao, MV (2007) Neurotrophins, synaptic plasticity and dementia. Curr Opin Neurobiol 17, 325330.Google Scholar
21Fumagalli, F, Racagni, G & Riva, MA (2006) Shedding light into the role of BDNF in the pharmacotherapy of Parkinson's disease. Pharmacogenomics J 6, 95104.Google Scholar
22Chun, HS, Son, JJ & Son, JH (2000) Identification of potential compounds promoting BDNF production in nigral dopaminergic neurons: clinical implication in Parkinson's disease. Neuroreport 11, 511514.Google Scholar
23Seifer, DB, Feng, B, Shelden, RM, et al. (2002) Brain-derived neurotrophic factor: a novel human ovarian follicular protein. J Clin Endocrinol Metab 87, 655659.CrossRefGoogle ScholarPubMed
24Pan, W, Banks, WA, Fasold, MB, et al. (1998) Transport of brain-derived neurotrophic factor across the blood–brain barrier. Neuropharmacology 37, 15531561.CrossRefGoogle ScholarPubMed
25Kramer, AF, Colcombe, SJ, McAuley, E, et al. (2005) Fitness, aging and neurocognitive function. Neurobiol Aging 26, Suppl. 1, 124127.CrossRefGoogle ScholarPubMed
26Colcombe, SJ, Kramer, AF, McAuley, E, et al. (2004) Neurocognitive aging and cardiovascular fitness: recent findings and future directions. J Mol Neurosci 24, 914.Google Scholar
27Kramer, AF, Hahn, S, Cohen, NJ, et al. (1999) Ageing, fitness and neurocognitive function. Nature 400, 418419.CrossRefGoogle ScholarPubMed
28Connolly, SK & Tamy, (2010) Caffeine modulates CREB-dependent gene expression in developing cortical neurons. Biochem Biophys Res Commun 397, 152156.Google Scholar
29Costa, MS, Botton, PH, Mioranzza, S, et al. (2008) Caffeine improves adult mice performance in the object recognition task and increases BDNF and TrkB independent on phospho-CREB immunocontent in the hippocampus. Neurochem Int 53, 8994.Google Scholar
30Alhaider, IA, Aleisa, AM, Tran, TT, et al. (2011) Sleep deprivation prevents stimulation-induced increases of levels of P-CREB and BDNF: protection by caffeine. Mol Cell Neurosci 46, 742751.CrossRefGoogle ScholarPubMed
31Heimbach, JT, Marone, PA, Hunter, JM, et al. (2010) Safety studies on products from whole coffee fruit. Food Chem Toxicol 48, 25172525.Google Scholar
32Yashin, YI, Nemzer, BV, Ryzhnev, VY, et al. (2010) Creation of a databank for content of antioxidants in food products by an amperometric method. Molecules 15, 74507466.CrossRefGoogle ScholarPubMed
33Borecki, IB, Higgins, M, Schreiner, PJ, et al. (1998) Evidence for multiple determinants of the body mass index: the National Heart, Lung, and Blood Institute Family Heart Study. Obes Res 6, 107114.CrossRefGoogle ScholarPubMed
34Zolodz, JAPA, Majerczak, K, Grandys, M, et al. (2008) Endurance training increases brain-derived neurotrophic factor concentration in young healthy men. J Physiol Pharmacol S17, 59, 199–132.Google Scholar
35Piccini, A, Marazziti, D, Del Debbio, A, et al. (2008) Diurnal variation of plasma brain-derived neurotrophic growth factor (BDNF) in humans. Chronobiol Int 25, 819826.Google Scholar
36Mullen, W, Nemzer, B, Ou, B, et al. (2011) The antioxidant and chlorogenic acid profiles of whole coffee fruits are influenced by the extraction procedures. J Agric Food Chem 59, 37543762.CrossRefGoogle ScholarPubMed
37International Organization for Standardization (ISO) (2005) Determination of Substances Characteristic of Green and Black Tea. Part 1: Content of Total Polyphenols in Tea – Colorimetric Method Using Folin–Ciocalteu Reagent. Geneva: ISO. ISO 14502-1.Google Scholar
38Chung, HY, Choi, HR, Park, HJ, et al. (2001) Peroxynitrite scavenging and cytoprotective activity of 2,3,6-tribromo-4,5-dihydroxybenzyl methyl ether from the marine alga Symphyocladia latiuscula. J Agric Food Chem 49, 36143621.CrossRefGoogle ScholarPubMed
39Huang, D, Ou, B, Hampsch-Woodill, M, et al. (2002) High-throughput assay of oxygen radical absorbance capacity (ORAC) using a multichannel liquid handling system coupled with a microplate fluorescence reader in 96-well format. J Agric Food Chem 50, 44374444.Google Scholar
40Ou, B, Hampsch-Woodill, M, Flanagan, J, et al. (2002) Novel fluorometric assay for hydroxyl radical prevention capacity using fluorescein as the probe. J Agric Food Chem 50, 27722777.Google Scholar
41Zhang, L, Huang, D, Kondo, M, et al. (2009) Novel high-throughput assay for antioxidant capacity against superoxide anion. J Agric Food Chem 57, 26612667.Google Scholar
42Elzinga, BM, Molendijk, ML, Oude Voshaar, RC, et al. (2011) The impact of childhood abuse and recent stress on serum brain-derived neurotrophic factor and the moderating role of BDNF Val66Met. Psychopharmacology 214, 319328.Google Scholar
43Larsen, MH, Mikkelsen, JD, Hay-Schmidt, A, et al. (2010) Regulation of brain-derived neurotrophic factor (BDNF) in the chronic unpredictable stress rat model and the effects of chronic antidepressant treatment. J Psychiatr Res 44, 808816.Google Scholar
44Advani, T, Koek, W & Hensler, JG (2009) Gender differences in the enhanced vulnerability of BDNF+/ −  mice to mild stress. Int J Neuropsychopharmacol 12, 583588.Google Scholar
45Capiotti, KM, Menezes, FP, Nazario, LR, et al. (2011) Early exposure to caffeine affects gene expression of adenosine receptors, DARPP-32 and BDNF without affecting sensibility and morphology of developing zebrafish (Danio rerio). Neurotoxicol Teratol 33, 680685.Google Scholar
46Bairam, A, Kinkead, R, Lajeunesse, Y, et al. (2010) Neonatal caffeine treatment does not induce long-term consequences on TrkB receptors or BDNF expression in chemosensory organs of adult rats. Neurosci Lett 468, 292296.CrossRefGoogle ScholarPubMed
47Xu, J, Rong, S, Xie, B, et al. (2010) Memory impairment in cognitively impaired aged rats associated with decreased hippocampal CREB phosphorylation: reversal by procyanidins extracted from the lotus seedpod. J Gerontol 65, 933940.CrossRefGoogle ScholarPubMed
48Fraga, CG & Oteiza, PI (2011) Dietary flavonoids: role of ( − )-epicatechin and related procyanidins in cell signaling. Free Radic Biol Med 51, 813823.CrossRefGoogle ScholarPubMed
49Terra, X, Pallares, V, Ardevol, A, et al. (2011) Modulatory effect of grape-seed procyanidins on local and systemic inflammation in diet-induced obesity rats. J Nutr Biochem 22, 380387.Google Scholar
50Narita, K, Hisamoto, M, Okuda, T, et al. (2011) Differential neuroprotective activity of two different grape seed extracts. PloS one 6, e14575.Google Scholar
51Fu, W, Lu, C & Mattson, MP (2002) Telomerase mediates the cell survival-promoting actions of brain-derived neurotrophic factor and secreted amyloid precursor protein in developing hippocampal neurons. J Neurosci 22, 10, 710719.CrossRefGoogle ScholarPubMed
52Niu C (2010) The neuroprotective signaling mechanisms of telomerase via the induction by brain-derived neurotrophic factor (BDNF) in nervous system injury. Postgraduate Thesis, University of Hong Kong.Google Scholar
53Wang, CCLT, Liao, WC, Yuan, SC, et al. (2009) Cigarette smoking and cognitive impairment: a 10 year cohort study in Taiwan. Arch Gerontol Geriatr 1, 143148.Google Scholar
Figure 0

Table 1 Amount of caffeine, polyphenols and procyanidins in extracts tested in the present study

Figure 1

Fig. 1 Blood levels of brain-derived neurotrophic factor (BDNF) collected from subjects treated with whole coffee fruit concentrate powder (WCFC), green coffee bean extract powder (N625), green coffee caffeine powder (N677), grape seed extract powder (N31) and placebo (silica). Data represent average percentage difference from administration (T0). * Mean value was significantly different compared with placebo by Student's t test (P< 0·05).

Figure 2

Fig. 2 Blood levels of brain-derived neurotrophic factor (BDNF) measured in non-treated subjects (placebo), subjects receiving 50 mg of chlorogenic acid or 100 mg whole coffee fruit concentrate powder (WCFC). Data are presented as the average percentage difference compared with baseline (T0). * Mean value was significantly different compared with placebo by Student's t test (P< 0·05).