Grape Seeds Extract as Brain Food: A Review

Abstract

Interest in the biological role of bioactive compounds present in medicinal herbs has increased over the last years. Of particular interest are plants that have an anti-Alzheimer activities. Several plants can be useful for Alzheimer (AD) management. Such as these which have anti-inflammatory activity, acetylcholinesterase (AChE) inhibitory action, antiapoptotic, slow the aggregation of amyloid peptide and antioxidant activities. Grape seed extract (GSE) is a complex mixture of several compounds, mostly represented by polyphenols and flavonoids. Their consumption is safe and is recognized to exert several health benefits. GS flavonoids have been associated with the reduced risk of chronic diseases, we present some findings on the potential benefits of GSE for the treatment of AD.

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International Journal of Pharmaceutical and Clinical Research 2017; 9(1): 77-85
ISSN- 0975 1556
Review Article
*Author for Correspondence: souadgengaihi@hotmail.co.uk
Grape Seeds Extract as Brain Food: A Review
Souad El Gengaihi*, Doha H Abou Baker
Medicinal and Aromatic Plant Dept., Pharmaceutical Division, National Research Centre, Dokki, 12311 Cairo, Egypt
Available Online: 25th January, 2017
ABSTRACT
Interest in the biological role of bioactive compounds present in medicinal herbs has increased over the last years. Of
particular interest are plants that have an anti-Alzheimer activities. Several plants can be useful for Alzheimer (AD)
management. Such as these which have anti-inflammatory activity, acetylcholinesterase (AChE) inhibitory action, anti-
apoptotic, slow the aggregation of amyloid peptide and antioxidant activities. Grape seed extract (GSE) is a complex
mixture of several compounds, mostly represented by polyphenols and flavonoids. Their consumption is safe and is
recognized to exert several health benefits. GS flavonoids have been associated with the reduced risk of chronic diseases,
we present some findings on the potential benefits of GSE for the treatment of AD.
Keywords: Grape seed extract, Flavonoids, Antioxidant, Alzheimer.
INTRODUCTION
Grape seed extract (GSE)
In Egypt, grapes are considered the second important crop
after citrus. GS is one of the by-products of wine
production, accounting for 38-52% of pomace on dry
weight basis. Its importance is due to its high polyphenol
content. These phenolic compounds are mostly known for
their antioxidant properties1-3. Grape seed oil ranged from
11.8 to 12 % which rich in oleic and linoleic acids and the
degree of unsaturation in the oils was over 70%. Alpha-
tocopherol was the most abundant tocopherol in the oil4.
The phenolic compounds in GSE can be divided into two
groups: (a) phenolic acids and related compounds and (b)
flavonoids. The most common phenolic acids in grape
include cinnamic acids (coumaric acid, caffeic acid, ferulic
acid, chlorogenic acid, and neochlorogenic acid) and
benzoic acids (p-hydroxybenzoic acid, protocatechuic
acid, vanillic acid, and gallic acid). Flavonoids include
colorless flavan-3-ols (such as catechin, epicatechin, their
polymers, and their ester forms with galactic acid or
glucose), colored flavanones (the most common flavanone
in food is quercetin), and red and blue anthocyanins5.
Grape seed proanthocyanidins extract (GSPE) are natural
antioxidants composed of various polyphenolic
compounds generally believed to protect against reactive
oxygen species (ROS)-mediated myocardial
ischemia/reperfusion injury and apoptosis of
cardiomyocytes2,6-9. While the use of GSPE has become
increasingly popular for health promotion and disease
prevention, concerns have been raised that high dose
GSPE may paradoxically induce toxicity10-13 high-dose
(500 μg/ml) GSPE may cause cytotoxicity associated with
caspase activation and increased apoptotic cell death14.
GSE popular with its a broad spectrum of therapeutic
effects such as Antioxidant2,7,15, anticancer16-23,
Cardioprotective effects8,24-29, Antimicrobial and antiviral
effects30-36, anti arthritic activity37, hepatoprotective
effects38-40 and Anti-Alzheimer activity41-46.
Grape flavonoids, can prevent AD both by inhibition of
neuro-inflammation and by reducing oxidative stress 47. In
a clinical trials, consumption of grape juice was also found
to enhance memory functions for older adults with early
memory decline48-49.
In this review, we present some findings from our
laboratory and those of others on the potential benefits of
GSE for the prevention and treatment of AD.
Alzheimer’s disease (AD)
In 1907, Alois Alzheimer, a German neuropathologist,
initially described the clinical findings of a 51-year-old
woman with a 41 year course of progressive dementia50.
AD is the most common form of adult onset dementia51. It
has been estimated that approximately 9 million
individuals could develop AD by the year 204052, unless
preventative strategies are found.
Environmental risk factors for AD is associated with
lifestyle factors, especially cigarette smoking53, fats and
alcohol, homocystine-related vitamins and oxidative stress
have a role in AD, as well as The concentration of
aluminum or silica in drinking water54 and elevated levels
of strontium, aluminum, iron, barium, mercury,
manganese cations combined with deficiencies of
magnesium/calcium in the food chains have been
suggested for initiation of free radicals mediated
progressive pathogenesis of neurodegeneration55-58.
AD is characterized by progressive memory loss.
Biochemically, AD is characterized by the deposition of
soluble Aβ produced the aggregation of the peptide
forming Aβ fibrils which exerts a toxic effect and
intracellular neurofibrillary tangles consist of
phosphotylated tau protein causing destabilization of cell
structure and loss of axons, dendrites and synapses59, also
DOI number: 10.25258/ijpcr.v9i1.8270

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neurotoxicity of Aβ occurs in conjugation with free
radicals which attack brain cell membrane, increase Ca+2
influx, initiate lipid peroxidation, protein oxidation, and
DNA oxidation observed in AD brains and damage
membrane and cytosolic proteins60-62.
In the brain, Alzheimer's disease is associated with
progressive synaptic and neuronal loss, in particular of
basal forebrain cholinergic neurons. In addition, the
Alzheimer brain shows accumulation and spreading of two
pathological features, i.e. intraneuronal neurofibrillary
tangles consisting of phosphorylated Tau protein, and extra
cellular senile plaques consisting of amyloid-β63.
Tau is a neuronal protein present in axons and dendrites
where it promotes tubulin polymerization and stabilizes
microtubules and thus contributes to cell structure and
cellular transport64. In addition, Tau involved in axonal
growth as indicated by the fact that neurons treated with
Tau antisense in vitro are unable to grow axons65.
Hyperphosphorylation of Tau as present in neurofibrillary
lesions characteristic in Alzheimer's disease, prevents Tau
from binding to microtubules causing destabilization of
cell structure thereby likely contributing to loss of axons,
dendrites and synapses58.
Amyloid β (Aβ) is generated by sequential proteolytic
cleavage of the transmembrane amyloid precursor protein
(APP) by membrane bound enzymes, called secretases.
The resulting length of the Aβ protein is dependent on
initial cleavage of the extracellular domain generating the
amyloidogenic end products Aβ 1-42 and Aβ 1-40 when
cleaved by β- and α-secretase, or the shorter non-
amyloidogenic p3 fragment produced by α- and γ-
secretase66. The Aβ 1-42 end product in free form is highly
neurotoxic, and forms aggregates that appear to be the
predominant species in senile plaques67. Also, the ratio
between soluble Aβ 1-42 and 1-40 in cerebrospinal fluid
correlates directly with the age of onset of Alzheimer's
disease68 (Fig1).
Mode of action of GSE as Anti-Alzheimer
Inhibition of AChE
In AD, many studies suggest an implication of an abnormal
focal accumulation of aluminum in the brain. In this
retrograde affection, aluminum may interfere with various
biochemical processes including Acetylcholine (Ach)
metabolism, and can thus act as a possible etiopathogenic
cofactor. Ach is involved in the signal transfer in the
synapses. After being delivered in the synapses. Ach in
brain is considered to be closely related to short term
p35 p25
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Tau
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LRP
γ-Secretase
β-Secretase
Amyloid
Precursor
Protein
α-Secretase
Activation of
Kinases
(PKC, ERK2, Src, RTK)
Late Onset
Alzheimer Disease Resistance to
Calpain Action
Destabilized
Microtubules
Impaired Axonal
Transport
Neuronal Death
Neuronal Death
Membrane Damage
Lipid Peroxidation
Alzheimer’s Disease Pathway
Neurofibrillary
Tangles (NFTs)
Senile Plaque
ROS
ROS
Figure 1

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memory, and the degree of Ach reduction was positively
correlated with dementia severity69. The clinical symptoms
of AD patients can be improved by increasing the function
of Ach system. So it is considered that Ach quantities are
a major symbol in judging spatial memory of rats. The
determination of key enzyme decompounding and/ or
compounding Ach is used to reflect indirectly Ach level.
Cholinesterases are a large family of enzymatic proteins
widely distributed throughout both neuronal and
nonneuronal tissues. Principal role of AChE is the
termination of nerve impulse transmission at the
cholinergic synapses by rapid hydrolysis of Ach70.
Inhibition of AChE serves as a strategy for the treatment
of AD could have a role in the pathogenesis of AD. The
deficiency in cholinergic neurotransmission in AD has led
to the development of cholinesterase inhibitors as the first-
line treatment for symptoms of this disease. Therefore, the
drugs approved for the AD therapy act by counteracting
the Ach deficiency, that is, they try to enhance the Ach
level in the brain71.
However, only tacrine, donepezil, rivastigmine, and
galanthamine have been approved by the Food and Drug
Administration in the United States72. These compounds
have been reported to have their adverse effects including
gastrointestinal disturbances and problems associated with
bioavailability73, which necessitates the interest in finding
better AChE inhibitors from natural resources. There has
been a lot of research on the biological effect of plants
traditionally used either in infusions or in traditional
remedies as AChE inhibitors in vitro74 and also as memory
enhancers in vivo71.
It has been demonstrated that treatment of Al-intoxicated
rats with GSE produced significant decrease in brain AchE
activity accompanied with significant increase in brain
Ach level in comparison with Al-intoxicated control
group. It has been demonstrated that GSE significantly
increases Ach release in the hippocampus75.
Supplementation with GSPE to treated animals
significantly (P< 0.05) attenuated the toxicity and
oxidative stress in brain evoked by Chlorpyrifos and also
restored AChE activity near to control level indicating
their ameliorating effect76-77.
Pervin et al.,78 investigate the AChE inhibitory activities of
grape skin anthocyanin (GSA) extract and demonstrate
that GSA administration significantly inhibited AChE in
the in vitro assay (IC50 = 363.61 µg/mL). Therefore, GSA
could be an excellent source for AD drugs79-80. Several
studies recently demonstrated that Anthocyanins including
(pelargonidin, delphinidin and cyanidin) also possess
antineurodegenerative properties, anticholinesterase
activity81-84 and also have beneficial effects on memory and
cognition, suggesting a clear neuroprotective role48,85-88.
Inhibition of Oxidative stress
There is growing evidence that oxidative stress is the main
risk factor closely related to the development of AD by
increasing Aβ production89. In view of this fact, natural
antioxidants could provide novel and safe therapeutic
options for these devastating disorders90. The
identification of novel antioxidants as potential
therapeutics have an important area of neuroscience
research. Amongst the most studied categories of natural
antioxidants have rapidly gained attention as viable
candidates for clinical testing in neurodegeneration and
acute neuronal injury such as stroke91-92.
A variety of antioxidant compounds derived from
nutraceuticals have demonstrated neuroprotective activity
in either in vitro or in vivo models of neuronal cell death.
The mechanisms of action have been suggested for the
neuroprotective effects antioxidant by scavenge free
radicals or they indirectly increase endogenous cellular
BDNF Pathway BDNF
SHC SOS
GRB2
PI3K
P
P
P
BAD P
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Ca2+
Ca2+
IP3
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BCLXL
BCL2
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Synaptic Plasticity and
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BAD
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K
B
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Ca2+
GAB1
Figure 2: BDNF Pathway Copyright ProteinLounge.com.

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antioxidant defenses, for example, via activation of the
nuclear factor erythroid-derived 2-related factor 2 (Nrf2)
transcription factor pathway and modulation of signal
transduction cascades or effects on gene expression93.
The remarkable effects of GSE may be related to the
inhibitory effect of monoamine oxidase activity in the
brain as described by Mizutani et al.94, which contribute
this activity as a mechanism by which resveratrol could
reduce oxidative stress, production of H2O2 and lipid
peroxidation.
It has been reported that GSE show improved viability of
neuron cells after H2O2-induced oxidative stress
demonstrated by reduction in lactate dehydrogenase
release or propidium iodide staining and also enhances
low-level production of intracellular nitric oxide in
primary rat astroglial cultures41,46,95-96.
It has been reported that resveratrol (grape flavonoid)
suppresses mitochondrial-induced ROS production in the
rat brain97, inhibits lipid peroxidation98, and protects
against oxidative DNA damage in stroke-prone
hypertensive rats94. In addition, Olas et al.99-100
documented that resveratrol was a powerful antioxidant,
able to interfere with advanced glycation end products,
mediated oxidative DNA damage, and was a useful agent
against vascular diseases where ROS were involved in
hypertension.
Effect of GSE on BDNF
BDNF (Brain-derived neurotrophic factor) is critical for
the survival and maintenance of sympathetic and sensory
neurons vital to learning, memory, and higher thinking.
BDNF itself is important for long-term memory101.
Without the nerve growth factor, the sympathetic and
sensory neurons will undergo apoptosis.
Sechi et al.,102 proposed that diet enriched with
antioxidants might be considered a valid alternative and a
valuable strategy to counteract aging-related cognitive
decline by modulating BDNF levels in plasma and serum.
Another study by El Gengaihi et al.,46 showed that,
administration of AlCl3 in rats led to significant reduction
in brain BCl-2 expression (35.0 Pg/mg) as well as BDNF
levels in AlCl3-intoxicated control (50.5 Pg/mg) compared
with those in control rats (52.8 and 99.6 Pg/mg,
respectively). After the treatment with GSE there are
remarkable increase both in BCl2 and BDNF (Fig 2).
Deaggregation of bata amyloid by GSE
GSE interferes with the aggregation of Aβ peptides and tau
into neurotoxic oligomeric Aβ aggregates and tau fibril
conformers Moreover, GSE may also destabilize
preformed Aβ and tau protein aggregates. GSPE blocks Aβ
fibril formation by interfering with protofibril formation,
and initial coil to α-helix/β-sheet secondary structure
transitions. Thus, GSE might modulate AD dementia by
beneficially modulating both Aβ and tau- mediated
neuropathologic mechanisms103-105.
Figure 3: GSPE might benefit AD by simultaneously interfering with the generation and stability of
neurotoxic Aβ and tau oligomeric conformers. A) GSPE interferes with protein-protein interactions necessary for the
assembly of Aβ peptides or tau proteins into neurotoxic oligomeric aggregates. B) GSE may intercalate into preformed
Aβ or tau oligomeric aggregates, which destabilizes the normally tight ultrastructure and leads to the dissociation of
Aβ aggregates and tau fibrils (Pasinetti and Ho 2010).

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Wang et al.,106-108 found that a naturally derived grape seed
polyphenolic extract (GSPE) can significantly inhibit
amyloid β-protein aggregation into high-molecular-weight
oligomers in vitro. When orally administered to Tg2576
mice, this polyphenolic preparation significantly
attenuates AD-type cognitive deterioration coincidentally
with reduced HMW soluble oligomeric Aβ in the brain,
suggested that grape seed-derived polyphenolics may be
useful agents to prevent or treat AD.
Grape flavonoids can reduce Aβ production either by
enhancing α-secretase (ADAM10) activity or by inhibiting
β-secretase. They can lead to the production of off-target
Aβ oligomers, thereby disrupting fibrillization, and inhibit
Aβ aggregation through metal-chelating activity. By acting
to improve cerebral vascular blood flow flavanols may
have the potential to reduce brain Aβ levels through a
peripheral sink mechanism (Fig. 3)109.
Porat et al.,110 suggested that GSPE may inhibit
oligomerization of Aβ. This inhibition would be highly
significant, because accumulation of soluble extracellular
high-molecular-weight oligomeric Aβ species in the brain
currently is considered a major risk factor for the onset and
progression of cognitive deterioration in AD111-119 Thus,
pharmacological strategies for the prevention of Aβ
oligomerization in the brain might result in improved
cognitive function in AD.
CONCLUSION
Findings presented in this review article support the
development of GSE as a preventative and/or therapeutic
agent in AD.
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