Neuroprotective effects of berry fruits on neurodegenerative diseases

Abstract

Recent clinical research has demonstrated that berry fruits can prevent age-related neurodegenerative
diseases and improve motor and cognitive functions. The berry fruits are also capable of
modulating signaling pathways involved in inflammation/cell survival and enhancing neuroplasticity.
The neuroprotective effects of berry fruits on neurodegenerative diseases are related to
phytochemicals such as anthocyanin, caffeic acid, catechin, quercetin, kaempferol and tannin. In
this review, we made an attempt to clearly describe the beneficial effects of various types of berries
as promising neuroprotective agents.

Full text

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NEURAL REGENERATION RESEARCH
August 2014,Volume 9,Issue 16 www.nrronline.org
Neuroprotective effects of berry fruits on
neurodegenerative diseases
1 Department of Food Science and Nutrition, College of Agricultural and Marine Sciences, Sultan Qaboos University, Muscat, Sultanate of Oman
2 Ageing and Dementia Research Group, Sultan Qaboos University, Muscat, Sultanate of Oman
3 College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Sultanate of Oman
4 College of Veterinary Medicine, Washington State University, Pullman, WA, USA
5 Department of Biochemistry and Biotechnology, Annamalai University, Tamilnadu, India
6 Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse
and Alcoholism, National Institutes of Health, Rockville, MD, USA
Corresponding author:
Musthafa Mohamed Essa, Ph.D.,
Department of Food Science and
Nutrition, P.O. 34, College of
Agricultural and Marine Sciences,
Sultan Qaboos University, Al-Khoud,
Muscat, P.C. 123, Sultanate of Oman,
drmdessa@squ.edu.om.
doi:10.4103/1673-5374.139483
http://www.nrronline.org/
Accepted: 2014-07-02
Selvaraju Subash
1, 2
, Musthafa Mohamed Essa
1, 2
, Samir Al-Adawi
2, 3
, Mushtaq A. Memon
4
, amilarasan Manivasagam
5
, Mohammed Akbar
6
Introduction
Many epidemiological studies have shown that regular avo-
noid rich fruit intake is associated with delayed Parkinson’s
disease (PD), Alzheimer’s disease (AD), ischemic diseases
and aging effects (Ono et al., 2003; Savaskan et al., 2003;
Marambaud et al., 2005; Alzheimer’s Association, 2008;
Pandey and Rizvi, 2009). Data from in vitro and animal stud-
ies suggest that among the sources of antioxidants, phyto-
chemicals in berry fruits (e.g., anthocyanin and caeic acid)
have a benecial role in brain aging and neurodegenerative
disorders because of their anti-oxidative, anti-inammatory,
anti-viral and anti-proliferative properties (Youdim et al.,
2001). Since oxidative stress and inammation appear to be
involved in brain aging and in neurodegenerative diseases
(Casadesus et al., 2002), it is theorized that increased con-
sumption of antioxidants may be eective in preventing or
ameliorating these changes. The neuroprotective effects of
strawberry, bilberry, black currant, blackberry, blueberry and
mulberry, were demonstrated by many scholars (Basu et al.,
2010; Rendeiro et al., 2012). Neuroinammatory processes
in the brain are believed to play a crucial role in the devel-
opment of neurodegenerative diseases, especially due to in-
creased production of reactive oxygen species (ROS) (Zheng
et al., 2003; Shaffer et al., 2006). Because of low activity of
antioxidant defense systems, the brain is susceptible to oxi-
dative stress more than other organs (Rahman, 2007; Uttara
et al., 2009). Moreover, many neurotransmitters are autoxi-
dized to generate ROS (Lau et al., 2003). In agreement with
these observations, there is evidence that increased oxidative
stress plays an important role in the pathogenesis of neuro-
degenerative diseases such as AD, PD, ischemic diseases and
aging (Esposito et al., 2012). e neuroprotective eects of
many polyphenols rely on their ability to cross the blood-
brain barrier and directly scavenge pathological concentra-
tions of reactive oxygen and nitrogen species and chelate
transition metal ions (Aquilano et al., 2008). Dierent poly-
phenolic compounds were shown to have scavenging activity
and the ability to activate key antioxidant enzymes in the
brain, thus breaking the vicious cycle of oxidative stress and
tissue damage (Lau et al., 2003; Esposito et al., 2012). ere
is a growing interest in the potential of natural polyphenols
in berries (Chen et al., 2013; Rios de Souza et al., 2014) to
improve memory, learning and general cognitive abilities.
Preclinical evidence has indicated that avonoids may exert
powerful actions on mammalian cognitive function and may
reverse age-related declines in memory and learning. ese
benecial eects are mainly in demand in preventing against
brain damage, such as ischemic and neurodegenerative dis-
Abstract
Recent clinical research has demonstrated that berry fruits can prevent age-related neurodegen-
erative diseases and improve motor and cognitive functions. The berry fruits are also capable
of modulating signaling pathways involved in inflammation, cell survival, neurotransmission
and enhancing neuroplasticity. The neuroprotective effects of berry fruits on neurodegenerative
diseases are related to phytochemicals such as anthocyanin, caffeic acid, catechin, quercetin, kae-
mpferol and tannin. In this review, we made an attempt to clearly describe the beneficial effects
of various types of berries as promising neuroprotective agents.
Key Words: nerve regeneration; berry fruit; neurodegenerative disease; neuroprotection; Alzheimer’s
disease; Parkinson’s disease; review; neural regeneration
Funding: This study was supported by a grant from the Research Councial of Sultanate of Oman,
No. RC/AGR/FOOD/11/01.
Subash S, Essa MM, Al-Adawi S, Memon MA, Manivasagam T, Akbar M. Neuroprotective effects of
berry fruits on neurodegenerative diseases. Neural Regen Res. 2014;9(16):1557-1566.

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Subash S, et al. / Neural Regeneration Research. 2014;9(16):1557-1566.
eases, reducing neuronal apoptosis, and improving memory,
learning and cognitive functions (Kovasova et al., 2010;
Angeloni et al., 2012). In this review, we made an attempt to
clearly describe the benecial eects of various types of ber-
ries as promising neuroprotective agents.
Strawberry
Strawberry tree (Arbutus unedo L.; Ericaceae family) is an
evergreen shrub, a native Mediterranean species that are
also cultivated in other regions of Eastern Europe. e wide
range of antioxidants (Tulipani et al., 2009) in strawberry
fruit makes strawberry as a “health promoting food”. The
most abundant antioxidants are caeic acid, ellagic acid, and
certain avonoids including anthocyanins, tannins, catechin,
quercetin, kaempferol, gallic acid derivatives, vitamins C, E
and carotenoids (Table 1 ; Hakkinen et al., 2009; Simirgiotis
et al., 2010; Karlund et al., 2014)
Seeram et al. (2001) studied the inhibitory eects of straw-
berries on cyclooxygenase (COX) in vitro, which is a key en-
zyme that plays an important role in the conversion of arachi-
donic acid to various eicosanoids involved in inammation.
ere are two isoforms of COX, namely COX-1 and COX-2.
Extracts from strawberries are moderately eective in inhibit-
ing COX-1, and are more potent inhibitors of COX-2
as well.
COX-2 is the main promoter of inflammatory prostaglan-
dins, while COX-1 is known to produce some gastroprotec-
tive prostaglandins. Selective inhibition of COX-2
could be
important because the inammatory process is involved in
the etiology of a wide range of neurodegenerative diseases,
including AD and PD (Ferencik et al., 2001).
Previous studies have shown that strawberry extracts oer
protection to age-induced decits by enhancing GTPase ac-
tivity, calcium content, oxotremorine-enhanced K+-evoked
striatal dopamine (DA) release, and alterations in membrane
rigidity and are eective in preventing the loss of sensitivity
in Purkinje cells (Joseph et al., 1998; Balk et al., 2006). In
addition, strawberry extracts can improve cognitive function
as shown by Morris water maze performance. Another study
has demonstrated that strawberry extracts can improve mo-
tor behavioral performance on the rod walking (Joseph et al.,
1998). These findings suggest that phytochemicals present
in strawberry benet age-related decits in addition to the
known benecial eects on cancer and other cardiovascular
diseases.
Young rats exposed to 56Fe particle radiation showed
neurochemical and behavioral changes which are similar
to those seen in aged organisms (Joseph et al., 2000). Some
scholars (Joseph et al., 1998, 1999; Bickord et al., 2000; You-
dim et al., 2001) have reported that maintaining rats for 2
months in antioxidant diets containing strawberry extracts
can prevent the occurrence of neurochemical and behavioral
changes that are characteristic of ageing. Precisely, maintain-
ing rats for 2 months in diets containing strawberry extracts
increased oxotremorine-enhanced dopamine release from
striatal slices when compared to control diet-fed animals.
In addition to the improvement in dopaminergic function,
there were improvements in motor behavior, spatial learning
and memory (Joseph et al., 1998, 1999; Bickord et al., 2000;
Youdim et al., 2001). A study done by Rabin et al. (2002)
showed that diet (2% strawberry extracts) reduced the ef-
fects of oxidative stress following exposure to 56Fe particles.
These results suggest that antioxidant-rich diet may serve
as eective countermeasures to prevent neurochemical and
behavioral changes following exposure to heavy particles.
Strawberry and vitamin E are shown to have equal protective
eects on age-related decits (Joseph et al., 1998).
Bilberry
Bilberries provide signicant health benets because of their
high levels of anthocyanins, flavonols, vitamins C, E, and
manganese and contain carotenoid, lutein, and zeaxanthin
(Murray et al., 2009; Nile et al., 2014). e biological func-
tion (including benets for eyes, mouth, gum health), power-
ful anti-inammatory (Luo et al., 2014), anti-hyperglycemic
(Stefanut et al., 2013) and antioxidative eects (Davarmanesh
et al., 2013; Baum et al., 2014; Calo and Marabini, 2014) can
protect blood vessels and improve blood circulation (Pan-
telidis et al., 2007; Szajdek et al., 2008).
A number of studies have shown that aging and partic-
ularly brain aging are associated with free radicals action
(Grady and Craik, 2000; Liu et al., 2003). Glutathione and its
related enzymes participate in the maintenance of oxidant
homeostasis and in the aging process and are associated
with a gradual pro-oxidizing shi in the glutathione redox
state. ere is a close link between glutathione metabolism
and oxidant homeostasis that can be manifested as learning
and synaptic plasticity deficits under the condition of low
glutathione content (Sayre et al., 2008; Johnson, 2012). ere
are few suitable animal models to study the supplemental
antioxidant functions in age-related decits in learning and
memory. OXYS rats with inherited features of accelerated
aging and high sensitivity to oxidative stress are potential ge-
netic murine models. ese rats have signicantly shortened
lifespan (28% shorter than Wistar rats). erefore, OXYS rats
have become a murine animal model to elucidate the basic
mechanisms of age-related changes in brain functions, such
as learning and cognitive deciencies in age-related diseases
(Obukhova et al., 2009). Kolosova et al. (2006) reported that
the level of glutathione in the brain of young OXYS rats is 1.3
times lower as compared to Wistar rats. At the same time,
superoxide dismutase activity was higher in 3-month-old
OXYS rats than in age-matched Wistar rats. It is known that
in many cells the expression of genes whose products exhibit
antioxidant activity might be induced by reactive oxygen
species generation. Therefore, a simultaneous increase in
superoxide dismutase activity and a decrease in glutathione
level might indicate the increased level of ROS generation in
the brain of young OXYS rats.
The above data support the theory that the reduction of
cellular expression and activity of antioxidant proteins is a
fundamental cause of the aging process and neurodegener-
ative diseases. Memory loss is accompanied but not neces-
sarily caused by accumulation of oxidative damage to lipids,
proteins, and nucleic acids, all of which can disrupt neuronal

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Subash S, et al. / Neural Regeneration Research. 2014;9(16):1557-1566.
Table 1 Structures of important active compounds of the berr y fruits
Compounds Fruits Chemical structures
Caffeic acid Strawberry & blueberry
Ellagic acid Strawberry
Anthocyanins Strawberry, bilberry, blackcurrant, blueberry, mulberry and blueberry
Catechin Strawberry
Quercetin Strawberry
Kaempferol Strawberry
Flavonols Bilberry, blackcurrant and blueberry
Foliate Blackberry
Cyaniding-3-O-glucoside Blackberry and mulberry
Salicylate Blackberry
Hydroxycinnamates Blueberry

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function. They also demonstrated that the bilberry extract
is eective in decreasing lipid peroxides and increasing su-
peroxide dismutase activity in the brain. Furthermore, long
term supplementation of bilberry extract prevents learning
and memory deficits in OXYS rats. It is known that high
eciency of bilberry extract might be provided by its avo-
noids, which have high free radical scavenging activity and
disease-fighting properties (Rahman, 2007; Uttara et al.,
2009).
Blackcurrant
Blackcurrant is a strong candidate fruit to provide neuropro-
tection in AD. Anthocyanins are the major group of poly-
phenols in blackcurrant, accounting for about 80% of the
total amount of quantied compounds (Ghosh and Konishi,
2007). β-Amyloid (Aβ)-induced formation of ROS is also in-
hibited by avonols from blackcurrant (Li et al., 2004). Poly-
phenolic substances present in blackcurrant fruits have been
reported for antioxidant, antimicrobial, antiviral, and anti-
bacterial properties (Krisch et al., 2009; Molan et al., 2010;
Bragoulo and Molan, 2011; Szachowicz-Peteleska et al., 2012;
Tabart et al., 2012; Vepsalainen et al., 2013). Vepsalainen et
al. (2013) investigated the eects of anthocyanin-rich black-
currant extracts on neuroprotection and amyloid precursor
protein (APP) expression in human SH-SY5Y neuroblastoma
cells overexpressing APP751 isoform under AD-related stress
conditions. ey also found that the cells which were treated
with anthocyanin-rich blackcurrant extracts experienced sig-
nicantly reduced ROS production. ese ndings indicate
that anthocyanin-rich blackcurrant extracts exhibit a bene-
cial eect through their promising antioxidant activity.
Polyphenols, which are abundant in bilberry and black-
currant, have been shown to inhibit the formation and
extension of Aβ brils and to destabilize the preformed Aβ
brils in vitro (Vepsalainen et al., 2013). ey also investigat-
ed the eects of both bilberry and blackcurrant-fed APdE9
mice; and found both berry extract-fed APdE9 mice showed
similar reductions in total APP-normalized APP C-terminal
fragments levels, while the dietary eects on soluble Aβ40 and
Aβ42 levels and the ratio of Aβ42/40 in the dorsal cortex were
different. Interestingly, bilberry supplementation reduced
both soluble Aβ40 and Aβ42 levels as compared to blackcur-
rant-fed mice, whereas a reduced ratio of insoluble Aβ42/40
and moderately increased soluble APPα levels were observed
in blackcurrant-fed mice, but not in bilberry-fed mice. ese
important ndings clearly suggest that the increased ratio of
Aβ42/40 is a key pathogenic feature and that soluble APPα is
known to exert neuroprotective effects. Berry supplements
may have an inhibitory eect on β-secretase expression, pre-
venting cognitive decline and mitigating AD-like pathology
in a mouse model of AD. On the other hand, the decreased
ratio of insoluble Aβ42/40 in blackcurrant-fed mice may be
attributed to the modulation of γ-secretase function than
β-secretase inhibition (Vepsalainen et al., 2013).
Bilberry and blackcurrant supplemented diets also atten-
uated behavioral abnormalities in APdE9 mice. Under a
stressful swimming condition, a black currant diet increased
swimming speed, ruling out the possibility that this is de-
rived from some kind of motor impairment. e most strik-
ing eect of berry extracts was observed in the food-moti-
vated spatial working memory task, in which both bilberry
and blackcurrant attenuated the APdE9 genotype-linked im-
pairment. A moderate benecial eect of the berry extracts
was also observed in the strategy of solving the Morris swim
task: both the time spent near the pool wall and search ro-
tations while swimming were decreased in the bilberry and
blackcurrant fed mice (Vepsäläinen et al., 2013). Interesting-
ly, hyperactivity was alleviated to some extent by both bilber-
ry and blackcurrant diets, but significance was found only
in the blackcurrant-fed mice. ese nding suggests that the
flavonols and anthocyanin-rich blackcurrant extracts exert
protective eects under stress conditions.
However, the fact that moderate alterations in long-lasting
supplementation of APdE9 mice with bilberry or blackcur-
rant revealed benecial eects on APP and Aβ metabolism.
In addition, these supplementations alleviated behavioral
abnormalities in a well-characterized AD mouse model.
Based on these results, it is anticipated that bilberry- and
blackcurrant-derived phytochemicals could display benefi-
cial neuroprotective eects on behavioral outcome and APP
processing and Aβ accumulation (Vepsalainen et al., 2013).
Blackberry
Blackberry fruits are well known to be a rich source of anti-
oxidants, rich polyphenols (Kaume et al., 2012) manganese,
folate, bers, cyaniding-3-O-glucoside, vitamin C, salicylate
and high tannin. The biological functions of blackberries
include anti-hyperglycemic (Stefanut et al., 2013), antioxida-
tive, antiseptic, antibacterial/antiviral, anticancer properties.
In addition, they can normalize cholesterol, delay the pro-
cess of aging, relieve pains, and strengthen blood circulation
(Jiao and Wang, 2000; Siriwoharn et al., 2006).
Tavares et al. (2013) reported that wild blackberries, brig-
antinus and vagabundus collected from Braganc (northeast
region of Portugal) demonstrated attainable neuroprotective
effects by reducing intracellular ROS levels, modulating
glutathione levels and inhibiting the occurrence of caspases
during treatments. These effects protected neuronal cells
against oxidative injury, one of the most important features
of neurodegeneration. In vitro studies have also reported that
blackberries have potent anti-inflammatory and antiprolif-
erative properties (Wang and Jiao, 2000; Dai et al., 2007). In
addition, the antioxidants present in these fruits improved
behavioral performance in motor neuron tests in aged rats.
The balance and fine motor coordination in cognitive test
were also improved in the Morris water maze, demonstrat-
ing the measures of spatial working memory and learning
(Shukitt-Hale et al., 2009).
Blueberry
Blueberries are a rich source of flavonoids, notably antho-
cyanins, caeic acid, avanols and hydroxycinnamates (Cao
et al., 1999; Prior et al., 2001; Wu et al., 2004; Gavrilova et
al., 2011; You et al., 2011). e consumption of blueberries

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Subash S, et al. / Neural Regeneration Research. 2014;9(16):1557-1566.
has been reported to prevent oxidative stress, inhibit inam-
mation (Sweeney et al., 2002) and kidney injury (Nair et al.,
2014), and improve vascular health (Erlund et al., 2008).
These beneficial effects have been attributed to their rela-
tively high avonoid content, in particular, anthocyanins. A
recent study has demonstrated that blueberry supplementa-
tion can alleviate age-related behavioral decits and high-fat
diet-related behavioral declines (Carey et al., 2014).
e protein kinases, such as MAP kinase (MAPK), extra-
cellular signal-regulated kinase (ERK) and transcriptional
activator cyclic-AMP response element binding protein
(CREB), are involved to mediate the beneficial effects of
learning and memory produced by various phytochemicals
present in blueberries. e imbalance in calcium homeosta-
sis and the accumulation of AB protein promote oxidative
stress, aging and neurodegeneration. Aβ alone or together
with glutamate, inhibits PKA and its downstream signaling
target CREB, in embryonic neurons. CREB is closely asso-
ciated with learning and memory at the synaptic sites that
are affected in AD. It is further complicated by age-related
dierences in memory, signal processing, and susceptibility
to ROS (Impey et al., 1999; Kuperstein and Yavin, 2002; Vi-
tolo et al., 2002). Brewer et al. (2010) reported that blueberry
extract treatment oers protection from Aβ42 in middle-aged
(neurons isolated in 10–12 months) and old neurons (neu-
rons isolated around 24 months) in a defined culture me-
dium. Blueberry extract treatment lowered Aβ42 toxicity in
middle-aged and old hippocampal neurons. Importantly,
blueberry extract induces a cellular upregulation of glutathi-
one synthesis, a major antioxidant that lowers production
of cellular ROS, indicating that the blueberry extract is a
potent antioxidant. This is confirmed by the findings that
Aβ treatment lowered the major redox buffer, glutathione,
consistent with oxidative depletion, but blueberry extract
treatment reversed this loss by increasing the level of gluta-
thione. e increase in glutathione level in old neurons aer
Aβ treatment is escorted by enhanced pERK signaling in an
age-dependent manner, showing the greatest increase in the
MAPK activity (Brewer, 1998). However, blueberry extract
treatment can reduce pERK activity (Brewer et al., 2013).
ERK1/2 is essential for protection against neurodegeneration
because of inammation/oxidative stress and is required for
memory formation. Studies have suggested that prolonged
activation of pERK signaling possibly has an adverse eect
and moderate pERK activity is protective and has benecial
eects. us, at least in part, blueberry extract may decrease
endogenous pERK expression level and its activity, because
the overall oxidative stress load and Aβ levels can be reduced
with blueberry extract. As mentioned above, blueberry
extract treatment can increase glutathione expression and
reduce ROS generation. Thus, submaximal ERK signaling
may reduce endogenous stress. Brewer et al. (1998) reported
that blueberry extract pretreatment prevents calcium dys-
regulation and inhibit CREB and ERK activities through
ROS stress response, suggesting that blueberry extract can
improve the cognitive function in aging rats by regulating
transient stress signaling and ROS generation.
A preclinical study has demonstrated that blueberry sup-
plementation enhances motor and memory performance in
aged animals (Youdim et al., 2000; Casadesus et al., 2004).
Changes in brain-derived neurotrophic factor-mediated
protein synthesis, such as Arc/Arg3.1, are directly related
to blueberry consumption. Inhibition of CREB/ brain-de-
rived neurotrophic factor pathway effectively blocks the
changes in spatial memory in the blueberry-supplemented
animals (Williams et al., 2008). Following blueberry feeding,
anthocyanins have been identified in the specific cerebral
regions responsible for cognitive function, including the
hippocampus and neocortex (Andres-Lacueva et al., 2005).
Furthermore, anthocyanins distribution in the hippocam-
pus might be related to increased neuronal signaling in this
region (Casadesus et al., 2000). Barros et al. (2006) conduct-
ed a study involving psychopharmacological screening to
evaluate potential eects of a lyophilized extract of dierent
cultivars from Vaccinium ashei, Reade (Ericaceae) berries,
which are commonly known as rabbit eye blueberries and
are shown to have memory-enhancing, anxiolytic and lo-
comotion increasing properties in mice, as well as the pro-
tective eects against free radical-induced DNA damage in
the brain. ese results are reliable with the hypothesis that
avonoids (including anthocyanins) can show benecial ef-
fects on cell signaling and decrease oxidative damage. ese
results also suggest that flavonoids might directly act on
cognitive function, which may help prevent age-related and
pathological degenerative processes in the brain.
Joseph et al. (1999) found that 8 week dietary supple-
mentation of blueberry extracts was effective in reversing
age-related deficits in the brain and behavioral dysfunc-
tiond in aged (19 months) F344 rats. In addition, blueberry
supplemented animals showed positive eects on cognitive
behavior, motor performance (e.g., rod walking and the ac-
celerating rotarod), carbachol-stimulated GTPase activity,
and oxotremorine enhanced DA release. A study showed
that aer 6 weeks of blueberry-supplemented diets, neuronal
loss in the hippocampus was reduced in rats with cerebral
ischemia (Sweeney et al., 2002). There is evidence that in
addition to Morris water maze performance, the cognitive
declines in object recognition were effectively reversed by
blueberry supplementation (Goyarzu et al., 2004). Ani-
mals treated with blueberry showed a signicantly reduced
caspase-3 activity in the ischemic hemisphere. Chronic treat-
ment with blueberry reduces ischemia/reperfusion-induced
apoptosis and cerebral infarction (Wang et al., 2005).
Stromberg et al. (2005) show that blueberry causes a rap-
id but transient increase of OX-6-positive microglia in the
striatum and the globus pallidus of normal F344 male rats.
Additionally, the number of striatal TH-positive nerve bers
was increased in animals fed with blueberry supplemented
diet. Supplementation of blueberries in adult mice (aged 3
months) improved performance in memory tasks and had a
protective effect on DNA damage in the hippocampus and
cerebral cortex (Barros et al., 2006). Short-term dietary sup-
plementation of antioxidant rich blueberries can decrease
the level of oxidative stress in brain regions and can amelio-

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Subash S, et al. / Neural Regeneration Research. 2014;9(16):1557-1566.
rate age-related decits in neuronal and behavioral functions
to generate a heat shock protein 70 mediated neuroprotec-
tive response to stress in rats. erefore, supplementeation of
blueberries shows benecial eects by increasing antioxidant
level, enhancing anti-inammatory activities and regulating
various signaling pathways at dierent time points (Galli et
al., 2006). A 2-month dietary supplementation of blueber-
ries alleviated deficits in learning performance induced by
bilateral hippocampal injections of kainic acid, reduced the
loss of CA1 pyramidal neurons (Duy et al., 2008), and re-
versed the decits in cognitive performance (Shukitt-Hale et
al., 2007). Short-term blueberry-enriched diet prevents and
reverses object recognition memory declines in aged Fisch-
er-344 rats (Malin et al., 2011). Joseph et al. (2003) showed
that amyloid precursor protein/presenilin-1 transgenic mice
that were given a diet containing blueberry extract from 4 to
12 months of age showed no behavioral deficits in Y-maze
performance. Krikorian et al. (2010) indicated that wild
blueberry juice supplementation for 12 weeks improved
memory function in old adults with mild memory decline.
e central cholinergic system is essential for the regula-
tion of cognitive functions (Sarter and Bruno, 1997; Silman
and Sussman, 2005; Zimmerman and Soreq, 2006). Agonists
of cholinergic receptors and inhibitors of acetylcholines-
terase have been extensively used to increase endogenous
acetylcholine levels and thus overcome cognitive deficits.
Acetylcholinesterase metabolizes acetylcholine to choline
and acetyl-coenzyme A. Papandreou et al. (2009) reported
that administration of polyphenol-rich wild blueberry ex-
tract to healthy adult mice attenuated brain oxidative stress
(MDA levels), increased brain ascorbate and glutathione
levels, and decreased acetylcholinesterase activity. Thus,
supplementation of polyphenols-concentrated blueberry
extract signicantly enhances the cognitive function of adult
mice by increasing cerebral antioxidant level and inhibiting
acetylcholinesterase activity. ese ndings stress the critical
impact of wild blueberry bioactive components on brain
function.
Shukitt-Hale et al. (2008) reported that blueberry polyphe-
nols attenuated kainic acid-induced learning impairments in
rats, which were similar to those observed in aged animals.
e reason for the similarity in behavioral decits between
aged and kainic acid-injected rats, as mentioned above,
might be the increase in inammation, which is a factor of
inducing cognitive decits. Blueberry polyphenols have an-
ti-inammatory actions. Young rats give a diet supplemented
with a 2% blueberry extract for 2 months, prior to the injec-
tion of an inammatory stimulus into the hippocampus, ex-
hibit signicantly less impairments in their spatial learning
and memory abilities.
Furthermore, rats fed with the blueberry diet prior to
kainic acid injection exhibited less activation of the inam-
matory marker MHC class II marker (OX-6), increased ex-
pression in the neurotrophic factor insulin-like growth fac-
tor-1 along with decreased levels of inammatory cytokines
interleukin-1β, tumor necrosis factor-α, and transcription
factor nuclear factor kappaB. us, the mechanism by which
blueberry polyphenols protects the brain is to decrease the
deleterious effects of an inflammatory stimulus by altering
the expression of inammation-related genes.
Experimental autoimmune encephalomyelitis presents
with pathological and clinical features similar to those of
multiple sclerosis, including inammation and neurodegen-
eration. A study by Xin et al. (2012) has demonstrated that
in relapsing-remitting experimental autoimmune enceph-
alomyelitis models, blueberry-supplemented mice showed
lower motor disability scores and improved cumulative and
nal motor scores compared to control diet-fed mice. ese
findings demonstrated that blueberry supplementation is
benecial in multiple experimental autoimmune encephalo-
myelitis models, suggesting that blueberries, which are easily
administered orally and well-tolerated, may provide benets
to multiple sclerosis patients.
Mulberry
Mulberries (Morus alba L., Moraceae) are used in oriental
traditional medicine for anti-inammatory, diuretic, antitus-
sive, antipyretic (Asano et al., 2001) and anti-hyperglycemic
purposes (Stefanut et al., 2013). High amounts of anthocy-
anins from berries are consumed in the common diet and
used in some therapeutic applications (Mitcheva et al., 1993;
Dugo et al., 2001). Cyanidin-3-O-β-d-glucopyranoside
(C3G), which is an aglycon of anthocyanin, has free radical
scavenging and inammation suppressing activities and of-
fers protection to an endothelial dysfunction (Seeram et al.,
2001; Kahkonen and Heinonen, 2003; Seraino et al., 2003).
In an effort to reduce the level of ROS-induced damage,
the mulberry fruit extract and C3G were evaluated to deter-
mine whether they can prevent ROS generation and reduce
the degree of neuronal damage. e data show that the neu-
roprotective eect of the mulberry fruit extract is the result
of C3G in the H2O2-induced oxidative damage in PC12 cells
(Kang et al., 2006). In oxygen-glucose-deprived PC12 cells,
C3G increased cell viability. In addition, C3G oered more
eective neuroprotection in oxygen-glucose deprivation-in-
duced cerebral ischemia than the mulberry fruit extract
at the same concentration (Kang et al., 2006). The result
suggests that C3G is a major neuroprotective compound in
the mulberry fruit extract in oxygen-glucose deprivation-in-
duced cerebral ischemic cytotoxicity in PC12 cells. In in vivo
experiments, mulberry fruit extract and C3G reduce infarct
volume in middle cerebral artery-occluded animal models.
Additional studies have demonstrated that the mulberry
fruit extract has neuroprotective eects in both in vitro and
in vivo ischemic oxidative stress models, suggesting that
C3G is a major neuroprotective constituent of the mulberry
fruit extract (Kang et al., 2006).
Conclusion
Oxidative stress and inflammation are major factors con-
tributing to aging and the development of age-related neu-
rodegenerative diseases. Numerous natural antioxidant/
anti-inammatory compounds found in plant food matrices,

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Subash S, et al. / Neural Regeneration Research. 2014;9(16):1557-1566.
like fruits, especially berries (such as strawberry, bilberry,
blackcurrant, blackberry, blueberry and mulberry) can oer
neuroprotective eects (Tabl e 2 ) (Essa et al., 2012; Subash et
al., 2014a,b,c). Furthermore, the berry fruit may exert their
effects directly through alterations in cell signaling to im-
prove/increase neuronal communication, calcium buering,
neuroprotective stress shock proteins, plasticity, antioxidant/
anti-inflammatory action, stress signaling pathways and
inhibition of acetylcholinesterase. ese modications, and
others that are being studied, may mediate the enhance-
ments in cognitive and motor behavioral performance by
berries. us, nutritional interventions rich in phytochemi-
cals (for example anthocyanins and caeic acid) such as ber-
ry fruits may be a valuable asset in preventing against aging
by reducing or delaying the development of age-related neu-
rodegenerative diseases (Figure 1). Extensive clinical trials
need to be done to further validate the eects of berry fruits
and bring novel therapeutic agents for brain-related diseases.
Author contributions: Essa MM, Al-Adawi S, Memom MA,
Manivasagam T and Akbar M designed this manuscript. Subash
S wrote the manuscript. Essa MM and Akbar M revised the man-
uscript. All authors approved the final version of this manuscript.
Conflicts of interest: None declared.
Table 2 Neuroprotective effects of berry fruits
Natural
compounds Class/mechanism/therapeutic mode erapeutic eect References
Strawberry •Stimulated guanine triphosphate-ase activity
•Reducing oxidative stress
•Cyclooxegenase inhibition
•Improving morris water maze performance
•Preventing neurochemical and behavioral
changes
•Anti-inammatory activity
Joseph et al. (1998, 1999)
Joseph et al. (1998, 1999); Bickford
et al. (2000); Youdim and Joseph
(2001); Rabin et al. (2002)
Seeram et al. (2001)
Bilberry and
blackcurrant
•Decreasing the ratio of insoluble amyloid
beta-42/40
•Alleviating behavioral abnormalities Vepsalainen et al. (2013)
Bilberry •Free radical scavenging activity •Alleviating memory decits Kovacsova et al. (2010)
Blackberry •Reducing intracellular reactive oxygen
species levels, modulating glutathione levels
and inhibiting caspases activity
•Improving behavioral performance in motor
tests and Morris water maze (cognitive test)
Shukitt-Hale et al. (2009);
Tavares et al. (2013)
Blueberry •Changes in brain-derived neurotrophic
factor
•Decreasing Aβ levels
•Decreasing the levels of interleukin-1β,
tumor necrosis factor-α and transcription
factor nuclear factor-kappaB
•Enhancing motor and memory performances
•Signicant cognitive enhancement
Youdim et al. (2000);
Casadesus et al. (2004)
Papandreou et al. (2009)
Mulberr y •Decreasing the infarct volume of the brain •Neuroprotection Kang et al. (2006)
Figure 1 Graphic representation showing the possible mechanism of berry fruits against neurodegenerative diseases (NDD).
NDD
Increased
inflammation
Increased
apoptosis
Impairments in memory
and behaviors
Increased oxidative stress
Berries

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Subash S, et al. / Neural Regeneration Research. 2014;9(16):1557-1566.
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Copyedited by Pohanka M, Colangelo AM, Li CH, Song LP, Zhao M