Neuroprotective effects of berry fruits on neurodegenerative diseases

Selvaraju Subash, Musthafa Mohamed Essa, Samir Al-Adawi,, Mushtaq A. Memon, Thamilarasan Manivasagam, Mohammed Akbar

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

Neuroprotective effects of berry fruits on neurodegenerative diseases

Selvaraju Subash1,2, Musthafa Mohamed Essa1,2, Samir Al-Adawi2,3, Mushtaq A. Memon4, Thamilarasan Manivasagam5, Mohammed Akbar6

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

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, neurotransmission 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 bene fi cial effects of various types of berries as promising neuroprotective agents.

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.

Introduction

Many epidemiological studies have shown that regular flavonoid 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 fromin vitroand animal studies suggest that among the sources of antioxidants, phytochemicals in berry fruits (e.g., anthocyanin and ca ff eic acid) have a bene fi cial role in brain aging and neurodegenerative disorders because of their anti-oxidative, anti-in flammatory, anti-viral and anti-proliferative properties (Youdim et al., 2001). Since oxidative stress and in flammation appear to be involved in brain aging and in neurodegenerative diseases (Casadesus et al., 2002), it is theorized that increased consumption of antioxidants may be e ff 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 flammatory processes in the brain are believed to play a crucial role in the development of neurodegenerative diseases, especially due to increased 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 oxidative stress more than other organs (Rahman, 2007; Uttara et al., 2009). Moreover, many neurotransmitters are autoxidized 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 neurodegenerative diseases such as AD, PD, ischemic diseases and aging (Esposito et al., 2012).e neuroprotective e ff ects of many polyphenols rely on their ability to cross the bloodbrain barrier and directly scavenge pathological concentrations of reactive oxygen and nitrogen species and chelate transition metal ions (Aquilano et al., 2008). Di ff erent polyphenolic 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 flavonoids may exert powerful actions on mammalian cognitive function and may reverse age-related declines in memory and learning.ese bene fi cial e ff ects are mainly in demand in preventing against brain damage, such as ischemic and neurodegenerative dis-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 fi cial e ff ects of various types of berries as promising neuroprotective agents.

Strawberry

Strawberry tree (Arbutus unedoL.; 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 ff eic acid, ellagic acid, and certain flavonoids 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 ff ects of strawberries on cyclooxygenase (COX)in vitro, which is a key enzyme that plays an important role in the conversion of arachidonic acid to various eicosanoids involved in in flammation.ere are two isoforms of COX, namely COX-1 and COX-2. Extracts from strawberries are moderately e ff ective in inhibiting COX-1, and are more potent inhibitors of COX-2 as well. COX-2 is the main promoter of inflammatory prostaglandins, while COX-1 is known to produce some gastroprotective prostaglandins. Selective inhibition of COX-2 could be important because the in flammatory 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 ff er protection to age-induced de fi cits by enhancing GTPase activity, calcium content, oxotremorine-enhanced K+-evoked striatal dopamine (DA) release, and alterations in membrane rigidity and are e ff 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 motor behavioral performance on the rod walking (Joseph et al., 1998). These findings suggest that phytochemicals present in strawberry bene fi t age-related de fi cits in addition to the known bene fi cial e ff ects on cancer and other cardiovascular diseases.

Young rats exposed to56Fe 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; Youdim 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, maintaining 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 effects of oxidative stress following exposure to56Fe particles. These results suggest that antioxidant-rich diet may serve as e ff ective countermeasures to prevent neurochemical and behavioral changes following exposure to heavy particles. Strawberry and vitamin E are shown to have equal protective e ff ects on age-related de fi cits (Joseph et al., 1998).

Bilberry

Bilberries provide signi fi cant health bene fi 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 function (including bene fi ts for eyes, mouth, gum health), powerful anti-in flammatory (Luo et al., 2014), anti-hyperglycemic (Stefanut et al., 2013) and antioxidative e ff ects (Davarmanesh et al., 2013; Baum et al., 2014; Calo and Marabini, 2014) can protect blood vessels and improve blood circulation (Pantelidis et al., 2007; Szajdek et al., 2008).

A number of studies have shown that aging and particularly 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 shiin 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 fi cits in learning and memory. OXYS rats with inherited features of accelerated aging and high sensitivity to oxidative stress are potential genetic murine models.ese rats have signi fi 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 fi 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 neurodegenerative diseases. Memory loss is accompanied but not necessarily caused by accumulation of oxidative damage to lipids, proteins, and nucleic acids, all of which can disrupt neuronal

function. They also demonstrated that the bilberry extract is e ff ective in decreasing lipid peroxides and increasing superoxide 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 ffi ciency of bilberry extract might be provided by its flavonoids, which have high free radical scavenging activity and disease-fighting properties (Rahman, 2007; Uttara et al., 2009).

Table 1 Structures of important active compounds of the berry fruits

Blackcurrant

Blackcurrant is a strong candidate fruit to provide neuroprotection in AD. Anthocyanins are the major group of polyphenols in blackcurrant, accounting for about 80% of the total amount of quanti fied compounds (Ghosh and Konishi, 2007). β-Amyloid (Aβ)-induced formation of ROS is also inhibited by flavonols from blackcurrant (Li et al., 2004). Polyphenolic substances present in blackcurrant fruits have been reported for antioxidant, antimicrobial, antiviral, and antibacterial 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 ff ects of anthocyanin-rich blackcurrant 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 signi fi cantly reduced ROS production.ese fi ndings indicate that anthocyanin-rich blackcurrant extracts exhibit a bene ficial e ff ect through their promising antioxidant activity.

Polyphenols, which are abundant in bilberry and blackcurrant, have been shown to inhibit the formation and extension of Aβ fi brils and to destabilize the preformed Aβ fi brilsin vitro(Vepsalainen et al., 2013).ey also investigated the e ff 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 ff ects on soluble Aβ40and Aβ42levels and the ratio of Aβ42/40in the dorsal cortex were different. Interestingly, bilberry supplementation reduced both soluble Aβ40and Aβ42levels as compared to blackcurrant-fed mice, whereas a reduced ratio of insoluble Aβ42/40and moderately increased soluble APPα levels were observed in blackcurrant-fed mice, but not in bilberry-fed mice.ese important fi ndings clearly suggest that the increased ratio of Aβ42/40is a key pathogenic feature and that soluble APPα is known to exert neuroprotective effects. Berry supplements may have an inhibitory e ff ect on β-secretase expression, preventing cognitive decline and mitigating AD-like pathology in a mouse model of AD. On the other hand, the decreased ratio of insoluble Aβ42/40in 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 attenuated behavioral abnormalities in APdE9 mice. Under a stressful swimming condition, a black currant diet increased swimming speed, ruling out the possibility that this is derived from some kind of motor impairment.e most striking e ff ect of berry extracts was observed in the food-motivated spatial working memory task, in which both bilberry and blackcurrant attenuated the APdE9 genotype-linked impairment. A moderate bene fi cial e ff 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 rotations while swimming were decreased in the bilberry and blackcurrant fed mice (Veps?l?inen et al., 2013). Interestingly, hyperactivity was alleviated to some extent by both bilberry and blackcurrant diets, but significance was found only in the blackcurrant-fed mice.ese fi nding suggests that the flavonols and anthocyanin-rich blackcurrant extracts exert protective e ff ects under stress conditions.

However, the fact that moderate alterations in long-lasting supplementation of APdE9 mice with bilberry or blackcurrant revealed bene fi cial e ff 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 beneficial neuroprotective e ff 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 antioxidants, rich polyphenols (Kaume et al., 2012) manganese, folate, fi bers, cyaniding-3-O-glucoside, vitamin C, salicylate and high tannin. The biological functions of blackberries include anti-hyperglycemic (Stefanut et al., 2013), antioxidative, antiseptic, antibacterial/antiviral, anticancer properties. In addition, they can normalize cholesterol, delay the process of aging, relieve pains, and strengthen blood circulation (Jiao and Wang, 2000; Siriwoharn et al., 2006).

Tavares et al. (2013) reported that wild blackberries, brigantinus 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 vitrostudies have also reported that blackberries have potent anti-inflammatory and antiproliferative 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, demonstrating the measures of spatial working memory and learning (Shukitt-Hale et al., 2009).

Blueberry

Blueberries are a rich source of flavonoids, notably anthocyanins, ca ff eic acid, flavanols 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 blueberrieshas been reported to prevent oxidative stress, inhibit in flammation (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 relatively high flavonoid content, in particular, anthocyanins. A recent study has demonstrated that blueberry supplementation can alleviate age-related behavioral de fi cits and high-fat diet-related behavioral declines (Carey et al., 2014).

A preclinical study has demonstrated that blueberry supplementation 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-derived 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 hippocampus might be related to increased neuronal signaling in this region (Casadesus et al., 2000). Barros et al. (2006) conducted a study involving psychopharmacological screening to evaluate potential e ff ects of a lyophilized extract of di ff erent cultivars fromVaccinium ashei, Reade (Ericaceae) berries, which are commonly known as rabbit eye blueberries and are shown to have memory-enhancing, anxiolytic and locomotion increasing properties in mice, as well as the protective e ff ects against free radical-induced DNA damage in the brain.ese results are reliable with the hypothesis that flavonoids (including anthocyanins) can show bene fi cial effects 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 supplementation of blueberry extracts was effective in reversing age-related deficits in the brain and behavioral dysfunctiond in aged (19 months) F344 rats. In addition, blueberry supplemented animals showed positive e ff ects on cognitive behavior, motor performance (e.g., rod walking and the accelerating rotarod), carbachol-stimulated GTPase activity, and oxotremorine enhanced DA release. A study showed that aer 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). Animals treated with blueberry showed a signi fi cantly reduced caspase-3 activity in the ischemic hemisphere. Chronic treatment with blueberry reduces ischemia/reperfusion-induced apoptosis and cerebral infarction (Wang et al., 2005).

Stromberg et al. (2005) show that blueberry causes a rapid 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 fi 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 supplementation of antioxidant rich blueberries can decrease the level of oxidative stress in brain regions and can amelio-rate age-related de fi cits in neuronal and behavioral functions to generate a heat shock protein 70 mediated neuroprotective response to stress in rats.erefore, supplementeation of blueberries shows bene fi cial e ff ects by increasing antioxidant level, enhancing anti-in flammatory activities and regulating various signaling pathways at di ff erent time points (Galli et al., 2006). A 2-month dietary supplementation of blueberries alleviated deficits in learning performance induced by bilateral hippocampal injections of kainic acid, reduced the loss of CA1 pyramidal neurons (Du ff y et al., 2008), and reversed the de fi cits in cognitive performance (Shukitt-Hale et al., 2007). Short-term blueberry-enriched diet prevents and reverses object recognition memory declines in aged Fischer-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.

Shukitt-Hale et al. (2008) reported that blueberry polyphenols 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 fi cits between aged and kainic acid-injected rats, as mentioned above, might be the increase in in flammation, which is a factor of inducing cognitive de fi cits. Blueberry polyphenols have anti-in flammatory actions. Young rats give a diet supplemented with a 2% blueberry extract for 2 months, prior to the injection of an in flammatory stimulus into the hippocampus, exhibit signi fi 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 flammatory marker MHC class II marker (OX-6), increased expression in the neurotrophic factor insulin-like growth factor-1 along with decreased levels of in flammatory 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 flammation-related genes.

Experimental autoimmune encephalomyelitis presents with pathological and clinical features similar to those of multiple sclerosis, including in flammation and neurodegeneration. A study by Xin et al. (2012) has demonstrated that in relapsing-remitting experimental autoimmune encephalomyelitis models, blueberry-supplemented mice showed lower motor disability scores and improved cumulative and fi nal motor scores compared to control diet-fed mice.ese findings demonstrated that blueberry supplementation is bene fi cial in multiple experimental autoimmune encephalomyelitis models, suggesting that blueberries, which are easily administered orally and well-tolerated, may provide bene fi ts to multiple sclerosis patients.

Mulberry

Mulberries (Morus alba L.,Moraceae) are used in oriental traditional medicine for anti-in flammatory, diuretic, antitussive, antipyretic (Asano et al., 2001) and anti-hyperglycemic purposes (Stefanut et al., 2013). High amounts of anthocyanins 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 flammation suppressing activities and offers 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 determine whether they can prevent ROS generation and reduce the degree of neuronal damage.e data show that the neuroprotective e ff 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 ff ered more e ff ective neuroprotection in oxygen-glucose deprivation-induced 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-induced cerebral ischemic cytotoxicity in PC12 cells. Inin vivoexperiments, 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 ff ects in bothin vitroandin vivoischemic 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 contributing to aging and the development of age-related neurodegenerative diseases. Numerous natural antioxidant/ anti-in flammatory compounds found in plant food matrices,like fruits, especially berries (such as strawberry, bilberry, blackcurrant, blackberry, blueberry and mulberry) can o ff er neuroprotective e ff ects (Table 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 improve/increase neuronal communication, calcium bu ff ering, neuroprotective stress shock proteins, plasticity, antioxidant/ anti-inflammatory action, stress signaling pathways and inhibition of acetylcholinesterase.ese modi fi cations, and others that are being studied, may mediate the enhancements in cognitive and motor behavioral performance by berries.us, nutritional interventions rich in phytochemicals (for example anthocyanins and ca ff eic acid) such as berry fruits may be a valuable asset in preventing against aging by reducing or delaying the development of age-related neurodegenerative diseases (Figure 1). Extensive clinical trials need to be done to further validate the e ff ects of berry fruits and bring novel therapeutic agents for brain-related diseases.

Table 2 Neuroprotective effects of berry fruits

Figure 1 Graphic representation showing the possible mechanism of berry fruits against neurodegenerative diseases (NDD).

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 manuscript. All authors approved the final version of this manuscript.

Con flicts of interest:None declared.

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Copyedited by Pohanka M, Colangelo AM, Li CH, Song LP, Zhao M

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.

10.4103/1673-5374.139483

http://www.nrronline.org/

Accepted: 2014-07-02