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Food and Nutrition Sciences, 2013, 4, 984-990
http://dx.dor.org/10.4236/fns.2013.49127 Published Online September 2013 (http://www.scirp.org/journal/fns)
Stimulatory Effect of Whole Coffee Fruit Concentrate
Powder on Plasma Levels of Total and Exosomal
Brain-Derived Neurotrophic Factor in Healthy Subjects:
An Acute Within-Subject Clinical Study
Tania Reyes-Izquierdo1*, Ruby Argumedo1, Cynthia Shu1, Boris Nemzer2, Zb Pietrzkowski1
1Applied BioClinical Inc., Irvine, USA; 2FutureCeuticals Inc., Momence, USA.
Email: *Tania@abclinicaldiscovery.com
Received June 2nd, 2013; revised July 2nd, 2013; accepted July 9th, 2013
Copyright © 2013 Tania Reyes-Izquierdo et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ABSTRACT
A pilot study by Reyes [1] previously showed that ingestion of single dose of whole coffee fruit concentrate (WCFC)
powder increased blood levels of brain derived neurotrophic factor (BDNF) during the first 60 minutes after ingestion.
In the present report, we performed a single dose, placebo-controlled, within-subject study to confirm and further inves-
tigate this effect. Twenty healthy subjects with ages ranging from 25 to 35 participated in this study. All fasted and
resting subjects received placebo on Day 1, WCFC on Day 2, and a cup of freshly brewed coffee on Day 3. Treatment
with WCFC resulted in a statistically significant increase in plasma BDNF compared to placebo (p = 0.0073) or coffee
(p = 0.0219) during first 60 minutes. In addition, e isolated exosomes from serum and found that they contained BDNF.
Furthermore, oral WCFC consumption acutely increased BDNF levels in serum exosomes. In summary, all presented
results justify further clinical investigation of WCFC as a tool to manage BDNF-dependent health conditions.
Keywords: Brain-Derived Neurotrophic Factor; Whole Coffee Fruit Concentrate; Coffee; Exosomes; Acute Effect
1. Introduction
Brain-derived neurotrophic factor (BDNF) is a member
of the neurotrophin family of growth factors, along with
nerve growth factor, neurotrophin N4/5, and neurotro-
phin NT6. BDNF has high affinity for the tropomy-
osin-related kinase B (TrkB) receptor [2,3]. This product
of the NTRK gene is expressed in several types of cells
and tissues with major expression in neural cells and car-
diomyocytes [4]. BDNF exerts several effects in the cen-
tral nervous system; it regulates the development and
differentiation of new neurons [5-7] and promotes neuron
survival [8-10]. Influences mood and depression [11-13],
sleep control [14] and modulates appetite [15,16]. In ad-
dition, alterations in BDNF have been identified in vari-
ous chronic neurodegenerative diseases [17]. Blood
BDNF declines during aging [18] and decreased levels
may be associated with depression [19]. Preclinical stud-
ies demonstrate that both BDNF and TrkB receptor ago-
nists have antidepressant effects in an animal model of
depression [20-23]. In humans suffering from depression,
blood levels of BDNF are lower than in healthy controls
[24].
BDNF may act through TrkB receptors not only in
brain cells, but also in several peripheral tissues. Blood
circulating BDNF and BDNF found in peripheral organs
and tissues may interact with the TrkB receptor to mo-
dulate glucose metabolism [25-27], energy expenditure
[25,27], total food intake [25], and stimulation of Glut 4
expression in muscle tissue [28]. Both central and pe-
ripheral administration of BDNF lowers blood glucose
and increases energy expenditure in diabetic animals [29].
Conversely, haploinsufficiency of the BDNF gene results
in hyperphagy and obesity [30,31].
Several types of cells within the human body express
BDNF mRNA [32] and the corresponding BDNF pep-
tides are stored for rapid release. BDNF can be rapidly
released from various types of blood cells including
platelets [33-35] peripheral blood mononuclear cells [36],
*Corresponding author.
Copyright © 2013 SciRes. FNS
Stimulatory Effect of Whole Coffee Fruit Concentrate Powder on Plasma Levels of Total and Exosomal
Brain-Derived Neurotrophic Factor in Healthy Subjects: An Acute Within-Subject Clinical Study
985
eosinophils [37-39], monocytes [40]. Interestingly, all of
these cells can release exosomes [41,42]. Exosomes are
40 - 50 nm vesicles found in various cell types (for re-
view, see Simons and Raposo [43]. Blood-circulating
exosomes carry mRNA, microRNA, and proteins char-
acteristic of the cells that release the exosomes.
Circulating exosomes can fuse with other cells and
transmit internal macromolecules, such as microRNA or
peptides [43,44]. Therefore, exosomes may function as a
communication vehicle between different cells and tis-
sues [45]. Recently, researchers were able to detect
exosomes in blood that had been released from brain
cells [46,47] indicating that exosomes can cross the
brain-blood barrier (BBB) [46,47]. Likewise, exosomes
released into blood may pass the BBB and deliver their
exosomal content [48]. Such an arrangement would sug-
gest that exosomes are of potential therapeutic value as a
means to deliver substances to brain that do not normally
cross the BBB [49].
We previously reported that WCFC acutely increases
blood levels of BDNF in a small number of healthy sub-
jects [1]. This preliminary study was limited by the small
number of participants and by the fact that the chosen
placebo, silica oxide, unexpectedly reduced BDNF levels
in blood. We now report the results of a larger clinical
trial that further clarifies the effect of WCFC on BDNF.
We also provide evidence that blood exosomes contain
BDNF and that treatment with WCFC may increase
exosomal BDNF content.
2. Materials and Methods
2.1. Materials
WCFC is a patented extract of whole coffee fruit (coffee
cherries) from Coffeaarabica. WCFC tested in this study
was provided by Future Ceuticals, Inc., Momence, IL,
USA. Chemical composition and polyphenol profile of
this material was previously reported [1]. Dulbecco’s
phosphate buffered saline (PBS) and water were pur-
chased from Sigma Chem. Co. (St. Louis, MO, USA).
Protein Low Binding microtubes were obtained from
Eppendorf (Hauppauge, NY, USA) and RC DC Protein
Assay Kit II was from Bio-Rad (Palo Alto, CA, USA).
Human BDNF Quantikine ELISA kits were from R&D
Systems (Minneapolis, MN USA). Heparin blood collec-
tion tubes were obtained from Ram Scientific Inc.
(Yonkers, NY) and lancets were purchased from Med-
lance® (Ozorkow, Poland). Placebo was empty gelatin
capsules obtained from Capsuline, Inc. (Pompano Beach,
FL, USA). Coffee was prepared in a Platinum B70
Keurig® brewer (Keurig Incorporated, Reading MA,
USA) and brewed to 150 mL cup size. Afterwards, 150
mL cold water was added per cup to cool down the cof-
fee for fast consumption. The pre-packed selected coffee
was San Francisco Bay Coffee One Cup for Keurig
K-Cup Brewers, French Roast (San Francisco, CA, USA)
which contains 130 ± 10 mg of caffeine.
This study was conducted according to the guidelines
put forth in the Declaration of Helsinki and all proce-
dures involving human subjects were approved by the
Institutional Review Board at Vita Clinical S.A. Aveni-
daCircunvalacion Norte #135, Guadalajara, JAL, Mexico
44,270 (Study protocol ABC-WCFC). All study subjects
were generally healthy and did not use any type of
medication or supplement for a period of 15 days prior to
the start of the study. The inclusion criteria required par-
ticipants to be between the ages of 25 and 35 and have a
body mass index between 18.5 and 24.9 kg/m² [50]. At
the time of the study, participants were free of rhinitis,
influenza, and any other symptoms of upper respiratory
infection. 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 experi-
mental procedures and written consent was obtained be-
fore administration of any study treatment.
2.2. Study Description
Twenty (20) subjects meeting inclusion criteria were
treated with placebo on Day 1, a single dose of WCFC
on Day 2, and 300 mL of freshly brewed coffee on the
Day 3. In all cases, subjects fasted for 12 h prior to the
first blood collection. Other than consuming one of the
given materials, patients had no intake per os during the
study period and remained calm and resting. One hun-
dred µL of finger blood were collected by finger punc-
ture and placed in Safe-T-Fill® Lithium heparin capillary
blood collection tubes (Ram Scientific Inc. Yonkers, NY)
at baseline (T0). Subsequent samples were collected
every 60 min (T60 and T120) after treatment.
2.3. BDNF Detection and Quantification
Heparin plasma was isolated from collected blood sam-
ples using centrifugation at 1000 × g for 10 min. Human
mature BDNF (aa129-247) was detected using a quanti-
tative sandwich ELISA immunoassay (R&D Systems;
Minneapolis, MN, USA) following the instructions pro-
vided. Final reactions were measured using a Molecular
Devices spectrophotometer (Sunnyvale, CA, USA) and
BDNF concentrations were determined based on a stan-
dard curve as described in the instruction.
2.4. Determination of Exosomal BDNF
(Clinical Case Experimentation)
For exosome isolation, 500 μL of blood were collected
Copyright © 2013 SciRes. FNS
Stimulatory Effect of Whole Coffee Fruit Concentrate Powder on Plasma Levels of Total and Exosomal
Brain-Derived Neurotrophic Factor in Healthy Subjects: An Acute Within-Subject Clinical Study
986
from finger puncture in serum collections tubes. Blood
was spun down at 1000 g for 10 min. Two-hundred fifty
µL of serum were used for exosome separation by pre-
cipitation using ExoQuick™ Exosome Precipitation Kit
(System Biosciences, Mountain View CA, USA) follow-
ing the instructions from the manufacturer. Briefly, 63
µL of exosome precipitation solution were added to 250
µL of serum. The samples were gently mixed to ensure
uniformity and then incubated at 4˚C for 30 min. After-
wards, samples were centrifuged at room temperature for
30 min at 1500 g. The supernatant was collected in a
clean tube while the pellet was spun again for 5 min at
1500 g and any remaining supernatant was removed.
Finally, the pellet was resuspended in 250 µL of Exo-
some Binding buffer (System Biosciences, Mountain
View, CA, USA) and incubated in an ice bath for 5 min
to complete the lytic process. BDNF contained in the
exosomal lysate was measured using the quantitative
sandwich ELISA immunoassay (R&D Systems; Min-
neapolis, MN, USA) previously described.
2.5. Lactate and Glucose Measurements
Blood lactate was measured using an Accutrend® Lactate
Point of Care (Roche, Mannheim, Germany) and BM-
Lactate Strips® (Roche, Mannheim, Germany). Twelve
µL of blood were loaded onto the strip and lactate was
read according to the instructions provided by the manu-
facturer. Glucose was measured using an Accu-Chek®
Compact Plus glucometer (Roche Diagnostics, Indian-
apolis, IN, USA) and Accu-Chek® test strips (Roche Di-
agnostics, Indianapolis, IN, USA). After blood was col-
lected for BDNF assays, fingers were wiped off and a
glucose test was performed on fresh blood. Glucose was
read according to the instructions provided by the manu-
facturer.
2.6. Statistical Analysis
As previously described [1], BDNF levels were com-
pared to a reference standard curve and each subject was
normalized to their own value measured at time zero (T0).
Results from each group were pooled and standard error
of the mean was used for each separate analysis. Plasma
BDNF levels for 60 and 120 minutes after treatment were
compared within experimental groups to baseline and
between experimental groups using a one-way ANOVA
with Tukey’s post hoc analysis. Descriptive analyses
were run in GraphPad® to derive mean and standard de-
viation for each group.
3. Results
Twenty healthy volunteers were recruited for this within-
subject crossover clinical study. On Day 1, participants
consumed an empty capsule labeled as placebo. On Day
2, 100 mg of WCFC was administered orally and on Day
3, they consumed fresh-brewed coffee. On each day,
blood samples were drawn at baseline and at 60 and 120
minutes after treatment. As shown in Figure 1, a single
100 mg dose of capsulated WCFC increased plasma
BDNF by 91% at 60 minutes and 66% at 120 minutes
compared to baseline (p < 0.001). Placebo increased
plasma BDNF by 5% (p = 0.5) at T60 and 26% (p = 0.02)
at T120 over baseline. Treatment with fresh coffee re-
sulted in 21% and 15% change at T60 (p = 0.1) and T120
(p = 0.2) over baseline, respectively (Figure 1). At 60
minutes, plasma BDNF in subjects treated with WCFC
was higher than those treated with placebo (p = 0.0073).
This difference diminished at 120 min (p = 0.1127).
WCFC treatment also increased BDNF levels signifi-
cantly more than fresh coffee consumption at 60 min (p =
0.02) and 120 min (p = 0.04). The coffee treatment did
not significantly alter BDNF levels when compared to
placebo at 60 min (p = 0.23) or 120 min (p = 0.138).
Blood levels of glucose (Figure 2A) and lactate (Figure
2B) were not changed by any of the three treatments
(placebo, WCFC, coffee) compared to baseline.
We were interested in determining whether treatment
with WCFC increases only free BDNF levels in the
blood or whether exosomal BDNF levels change as well.
After the within-subject crossover study, we selected one
participant at random to receive an additional dose of
WCFC. We collected serum samples at T0, T60 and
T120 as before. The exosome fraction was isolated using
standard procedures provided with the exosome isolation
kit. BDNF levels in the exosome fraction and remaining
serum from one volunteer are presented in Figure 3.
0%
50%
100%
150%
200%
250%
300%
Placebo WCFC Coffee
Day1Day2Day3
n=20 n=20 n=20
BDNF[%Change]
Treatments
T0
T60
T120
**
*
Figure 1. The effect of WCFC on BDNF. Plasma BDNF le-
vels were measured at baseline (T0), 60 (T60) and 120 (T120)
min after treatment. Subjects were treated with Placebo
(Day 1), 100 mg WCFC (Day 2) and 300 mL of diluted cof-
fee (Day 3). Data are presented as the average percentage
difference compared to baseline. *Mean value of WCFC
treatment was significantly different when compared with
placebo (p = 0.007) and coffee (p = 0.02) at T60. Results
were not significant at T120 when compared to the placebo
(p = 0.11), however, they are significant when compared to
coffee (p = 0.04).
Copyright © 2013 SciRes. FNS
Stimulatory Effect of Whole Coffee Fruit Concentrate Powder on Plasma Levels of Total and Exosomal
Brain-Derived Neurotrophic Factor in Healthy Subjects: An Acute Within-Subject Clinical Study
987
0
25
50
75
100
Placebo WCFC Coffee
Day1Day2Day3
n=20 n=20 n=20
Glucose(dl/L)
Treatments
T0
T60
T120
0%
50%
100%
150%
Placebo WCFC Coffee
Day1Day2Day3
n=20 n=20 n=20
Lactate[%Change]
Trea tm ent s
T0
T60
T12
0
A
B
Figure 2. Blood glucose levels (A) and lactate levels (B) re-
mained unchanged at baseline, 60 and 120 min after treat-
ment with placebo (Day 1), WCFC (Day 2) and coffee (Day
3). No significant differences were observed between treat-
ments or over time.
0
100
200
300
400
500
t0 t60 t120
BDNF(pg/mL)
TimePoints
Serum
Exosome
s
Figure 3. Exosomal BDNF after treatment with WCFC.
Exosomes were isolated from serum of one volunteer at
baseline and at 60 and 120 minutes after treatment with
WCFC. Preliminary results suggest that exosomal BDNF is
increased after treatment.
BDNF was present in exosomes before treatment at T0.
After 60 minutes, one dose of WCFC increased serum
BDNF by 54% and exosomal BDNF by 206%. The ini-
tial WCFC-induced increase in serum BDNF declined at
120 minutes (32% over baseline) as did exosomal BDNF
(39% over baseline). This clinical case result suggests
that acute treatment with WCFC may increase the
amount of exosomal BDNF in blood; however this re-
quires further investigation since data presented here are
from a single study participant.
4. Discussion
We report that a single dose of WCFC nearly doubles the
amount of BDNF in the blood after 60 minutes with sus-
tained effects for at least two hours after treatment. This
confirms and extends the results of our previous work [1].
This effect was not seen with freshly brewed coffee over
the same time, a control that was not tested previously.
This result is consistent, however, with our previous ob-
servation that coffee beans or green coffee extracts con-
taining various amounts of caffeine do not raise BDNF
levels in blood [1]. Since WCFC is an extract of whole
coffee fruit, it does not contain BDNF. Thus, WCFC
could be considered to be a stimulator of endogenous
BDNF release from cells. As previously described, there
are several types of mammalian cells capable of releasing
BDNF. However, it remains to be determined which cells
are stimulated by WCFC and by what mechanism.
In a previous study, we reported that the use of silica
oxide as a placebo, slightly decreased levels of blood
BDNF [1]. In the current study, empty gelatin capsules
were used as placebo, showing a slight, but not signifi-
cant increase in plasma BDNF (5%) at T60, whilst
BDNF blood levels increased up to 28% at T120. Coffee
had no significant effect on BDNF at T60 and T120.
While fasting is known to increase BDNF levels in brain
[51,52], this effect for serum in healthy individuals has
not been clearly shown. In addition, studies of long term
fasting on serum BDNF levels have yielded conflicting
results [53,54].
Since study participants fasted 12 hours prior to the
start of the study, we monitored blood glucose for hypo-
glycemia. We also wanted to learn if WCFC affects
blood levels of glucose or lactate. We confirmed our pre-
vious finding that WCFC does not affect glucose or lac-
tate [1]. It is important to mention, that this study was
conducted on healthy subjects. It is unclear what effect
WCFC would have on subjects with chronic conditions,
until additional trials have been conducted.
An acute increase in blood levels of BDNF may indi-
cate that BDNF is released into bloodstream from cells
[43]. Therefore, we hypothesized that at least part of the
plasma BDNF detected was released from exosomes de-
rived from blood cells. We report for the first time that
blood-circulating BDNF may exist as both free BDNF
and contained within exosomes. Free BDNF sharply in-
creased one hour after WCFC treatment and began to
return to baseline after two hours, as did exosomal
BDNF. Further studies are needed to confirm that BDNF
circulates in blood as both free BDNF and exosomal
BDNF since this was the result obtained in a single sub-
ject (clinical case experiment). However, the initial result
is encouraging. Since exosomes have the ability to cross
the BBB [43], it would be interesting to study the effect
of WCFC on BDNF-mediated brain functionalities such
as cognitive activity [47], appetite control [55], or modu-
lation of neurodegenerative conditions [47,49,56,57].
Copyright © 2013 SciRes. FNS
Stimulatory Effect of Whole Coffee Fruit Concentrate Powder on Plasma Levels of Total and Exosomal
Brain-Derived Neurotrophic Factor in Healthy Subjects: An Acute Within-Subject Clinical Study
988
5. Acknowledgements
The present study was funded by Futureceuticals, Inc. T.
R.-I. conducted the experimental work, analysed the data
and led the manuscript writing. R. A. and C. S. per-
formed serum tests and helped in the data analysis. B. N.
designed and conducted all the chemical analysis. Z. P.
designed and directed the study. We express our grati-
tude to John Hunter and Brad Evers (Future Ceuticals)
for their comments and suggestions in the preparation of
this article. We would like to thank Michael Sapko for
his help in editing the manuscript. All authors declare
that they have no conflicts of interest.
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