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 ; data from in vitro and animal studies suggest that among the sources of antioxidants , phytochemicals in berry fruits ( e.g. , anthocyanin and caffeic acid ) have a beneficial role in brain aging and neurodegenerative disorders because of their anti - oxidative , anti - inflammatory , anti - viral and anti - proliferative properties ( youdim et al . , 2001 ) . since oxidative stress and inflammation 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 effective 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 . , neuroinflammatory 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 ) . the neuroprotective effects of many polyphenols rely on their ability to cross the blood - brain barrier and directly scavenge pathological concentrations of reactive oxygen and nitrogen species and chelate transition metal ions ( aquilano et al . , 2008 ) . different 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 ) . there is a growing interest in the potential of natural polyphenols in berries ( chen et al . , 2013 ; rios de souza et al . preclinical evidence has indicated that flavonoids may exert powerful actions on mammalian cognitive function and may reverse age - related declines in memory and learning . these beneficial effects are mainly in demand in preventing against brain damage , such as ischemic and neurodegenerative diseases , reducing neuronal apoptosis , and improving memory , learning and cognitive functions ( kovasova et al . , 2010 ; angeloni et al . , , we made an attempt to clearly describe the beneficial effects of various types of berries as promising neuroprotective agents . 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 . the most abundant antioxidants are caffeic 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 . , ( 2001 ) studied the inhibitory effects 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 inflammation . extracts from strawberries are moderately effective 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 inflammatory 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 offer protection to age - induced deficits by enhancing gtpase activity , calcium content , oxotremorine - enhanced k - evoked striatal dopamine ( da ) release , and alterations in membrane rigidity and are effective in preventing the loss of sensitivity in purkinje cells ( joseph et al . , 1998 ; 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 benefit age - related deficits in addition to the known beneficial effects on cancer and other cardiovascular diseases . young rats exposed to fe 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 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 . ( 2002 ) showed that diet ( 2% strawberry extracts ) reduced the effects of oxidative stress following exposure to fe particles . these results suggest that antioxidant - rich diet may serve as effective countermeasures to prevent neurochemical and behavioral changes following exposure to heavy particles . strawberry and vitamin e are shown to have equal protective effects on age - related deficits ( joseph et al . , 1998 ) . bilberries provide significant health benefits because of their high levels of anthocyanins , flavonols , vitamins c , e , and manganese and contain carotenoid , lutein , and zeaxanthin ( murray et al . , 2009 ; the biological function ( including benefits for eyes , mouth , gum health ) , powerful anti - inflammatory ( luo et al . , 2014 ) , anti - hyperglycemic ( stefanut et al . , 2013 ) and antioxidative effects ( davarmanesh et al . , 2013 ; baum et al . , 2014 ; calo and marabini , 2014 ) can protect blood vessels and improve blood circulation ( pantelidis et al . 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 shift in the glutathione redox state . there 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 ) . there are few suitable animal models to study the supplemental antioxidant functions in age - related deficits in learning and memory . oxys rats with inherited features of accelerated aging and high sensitivity to oxidative stress are potential genetic murine models . these rats have significantly shortened lifespan ( 28% shorter than wistar rats ) . therefore , 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 deficiencies in age - related diseases ( obukhova et al . , 2009 ) . ( 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 effective 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 efficiency 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 . anthocyanins are the major group of polyphenols in blackcurrant , accounting for about 80% of the total amount of quantified compounds ( ghosh and konishi , 2007 ) . -amyloid ( a)-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 ) ( 2013 ) investigated the effects 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 . they also found that the cells which were treated with anthocyanin - rich blackcurrant extracts experienced significantly reduced ros production . these findings indicate that anthocyanin - rich blackcurrant extracts exhibit a beneficial effect through their promising antioxidant activity . polyphenols , which are abundant in bilberry and blackcurrant , have been shown to inhibit the formation and extension of a fibrils and to destabilize the preformed a fibrils in vitro ( vepsalainen et al . , 2013 ) . they also investigated the effects 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 effects on soluble a40 and a42 levels and the ratio of a42/40 in the dorsal cortex were different . interestingly , bilberry supplementation reduced both soluble a40 and a42 levels as compared to blackcurrant - fed mice , whereas a reduced ratio of insoluble a42/40 and moderately increased soluble app levels were observed in blackcurrant - fed mice , but not in bilberry - fed mice . these important findings clearly suggest that the increased ratio of a42/40 is a key pathogenic feature and that soluble app is known to exert neuroprotective effects . berry supplements may have an inhibitory effect on -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 a42/40 in blackcurrant - fed mice may be attributed to the modulation of -secretase function than -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 . the most striking effect 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 beneficial effect 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 ( vepslinen et al . , interestingly , hyperactivity was alleviated to some extent by both bilberry and blackcurrant diets , but significance was found only in the blackcurrant - fed mice . these finding suggests that the flavonols and anthocyanin - rich blackcurrant extracts exert protective effects under stress conditions . however , the fact that moderate alterations in long - lasting supplementation of apde9 mice with bilberry or blackcurrant revealed beneficial effects on app and a 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 effects on behavioral outcome and app processing and a accumulation ( vepsalainen et al . , 2013 ) . blackberry fruits are well known to be a rich source of antioxidants , rich polyphenols ( kaume et al . , 2012 ) manganese , folate , fibers , 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 ) . ( 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 vitro studies 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 ) . blueberries are a rich source of flavonoids , notably anthocyanins , caffeic acid , flavanols and hydroxycinnamates ( cao et al . , 1999 ; the consumption of blueberries has been reported to prevent oxidative stress , inhibit inflammation ( 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 deficits and high - fat diet - related behavioral declines ( carey et al . , 2014 ) . the protein kinases , such as map kinase ( mapk ) , extracellular 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 . the imbalance in calcium homeostasis and the accumulation of ab protein promote oxidative stress , aging and neurodegeneration . a alone or together with glutamate , inhibits pka and its downstream signaling target creb , in embryonic neurons . creb is closely associated with learning and memory at the synaptic sites that are affected in ad . it is further complicated by age - related differences in memory , signal processing , and susceptibility to ros ( impey et al . , 1999 ; ( 2010 ) reported that blueberry extract treatment offers protection from a42 in middle - aged ( neurons isolated in 1012 months ) and old neurons ( neurons isolated around 24 months ) in a defined culture medium . importantly , blueberry extract induces a cellular upregulation of glutathione 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 a treatment lowered the major redox buffer , glutathione , consistent with oxidative depletion , but blueberry extract treatment reversed this loss by increasing the level of glutathione . the increase in glutathione level in old neurons after a 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 inflammation / oxidative stress and is required for memory formation . studies have suggested that prolonged activation of perk signaling possibly has an adverse effect and moderate perk activity is protective and has beneficial effects . thus , at least in part , blueberry extract may decrease endogenous perk expression level and its activity , because the overall oxidative stress load and a levels can be reduced with blueberry extract . as mentioned above ( 1998 ) reported that blueberry extract pretreatment prevents calcium dysregulation 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 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 . 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 ) . ( 2006 ) conducted a study involving psychopharmacological screening to evaluate potential effects of a lyophilized extract of different cultivars from vaccinium 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 effects against free radical - induced dna damage in the brain . these results are reliable with the hypothesis that flavonoids ( including anthocyanins ) can show beneficial effects on cell signaling and decrease oxidative damage . these results also suggest that flavonoids might directly act on cognitive function , which may help prevent age - related and pathological degenerative processes in the brain . ( 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 effects 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 after 6 weeks of blueberry - supplemented diets , neuronal loss in the hippocampus was reduced in rats with cerebral ischemia ( sweeney et al . 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 ) . chronic treatment with blueberry reduces ischemia / reperfusion - induced apoptosis and cerebral infarction ( wang et al . , 2005 ) . ( 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 fibers 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 ameliorate age - related deficits in neuronal and behavioral functions to generate a heat shock protein 70 mediated neuroprotective response to stress in rats . therefore , supplementeation of blueberries shows beneficial effects by increasing antioxidant level , enhancing anti - inflammatory activities and regulating various signaling pathways at different 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 ( duffy et al . , 2008 ) , and reversed the deficits 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 ) . ( 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 . 2010 ) indicated that wild blueberry juice supplementation for 12 weeks improved memory function in old adults with mild memory decline . the central cholinergic system is essential for the regulation of cognitive functions ( sarter and bruno , 1997 ; silman and sussman , 2005 ; zimmerman and soreq , 2006 ) . agonists of cholinergic receptors and inhibitors of acetylcholinesterase 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 extract 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 significantly enhances the cognitive function of adult mice by increasing cerebral antioxidant level and inhibiting acetylcholinesterase activity . these findings stress the critical impact of wild blueberry bioactive components on brain function . 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 . the reason for the similarity in behavioral deficits between aged and kainic acid - injected rats , as mentioned above , might be the increase in inflammation , which is a factor of inducing cognitive deficits . young rats give a diet supplemented with a 2% blueberry extract for 2 months , prior to the injection of an inflammatory stimulus into the hippocampus , exhibit significantly 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 inflammatory marker mhc class ii marker ( ox-6 ) , increased expression in the neurotrophic factor insulin - like growth factor-1 along with decreased levels of inflammatory cytokines interleukin-1 , tumor necrosis factor- , and transcription factor nuclear factor kappab . thus , the mechanism by which blueberry polyphenols protects the brain is to decrease the deleterious effects of an inflammatory stimulus by altering the expression of inflammation - related genes . experimental autoimmune encephalomyelitis presents with pathological and clinical features similar to those of multiple sclerosis , including inflammation 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 final motor scores compared to control diet - fed mice . these findings demonstrated that blueberry supplementation is beneficial in multiple experimental autoimmune encephalomyelitis models , suggesting that blueberries , which are easily administered orally and well - tolerated , may provide benefits to multiple sclerosis patients . mulberries ( morus alba l. , moraceae ) are used in oriental traditional medicine for anti - inflammatory , 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--d - glucopyranoside ( c3 g ) , which is an aglycon of anthocyanin , has free radical scavenging and inflammation suppressing activities and offers protection to an endothelial dysfunction ( seeram et al . , 2003 ) . in an effort to reduce the level of ros - induced damage , the mulberry fruit extract and c3 g were evaluated to determine whether they can prevent ros generation and reduce the degree of neuronal damage . the data show that the neuroprotective effect of the mulberry fruit extract is the result of c3 g in the h2o2-induced oxidative damage in pc12 cells ( kang et al . , 2006 ) . in addition , c3 g offered more effective 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 c3 g is a major neuroprotective compound in the mulberry fruit extract in oxygen - glucose deprivation - induced cerebral ischemic cytotoxicity in pc12 cells . in in vivo experiments , mulberry fruit extract and c3 g reduce infarct volume in middle cerebral artery - occluded animal models . additional studies have demonstrated that the mulberry fruit extract has neuroprotective effects in both in vitro and in vivo ischemic oxidative stress models , suggesting that c3 g is a major neuroprotective constituent of the mulberry fruit extract ( kang et al . , 2006 ) . oxidative stress and inflammation are major factors contributing to aging and the development of age - related neurodegenerative diseases . numerous natural antioxidant / anti - inflammatory compounds found in plant food matrices , like fruits , especially berries ( such as strawberry , bilberry , blackcurrant , blackberry , blueberry and mulberry ) can offer neuroprotective effects ( table 2 ) ( essa et al . , 2012 ; subash et al . furthermore , the berry fruit may exert their effects directly through alterations in cell signaling to improve / increase neuronal communication , calcium buffering , neuroprotective stress shock proteins , plasticity , antioxidant / anti - inflammatory action , stress signaling pathways and inhibition of acetylcholinesterase . these modifications , and others that are being studied , may mediate the enhancements in cognitive and motor behavioral performance by berries . thus , nutritional interventions rich in phytochemicals ( for example anthocyanins and caffeic 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 effects of berry fruits and bring novel therapeutic agents for brain - related diseases . neuroprotective effects of berry fruits graphic representation showing the possible mechanism of berry fruits against neurodegenerative diseases ( ndd ) .