**3. Active metabolites from berries with pharmacological activity**

Berries are rich in phytochemicals such as minerals, vitamins, fatty acids, and dietary fibers and specifically contain provitamin A, minerals, vitamin C, and B complex vitamins. Additionally, fruits contain soluble solids, fructose, and chemopreventive agents as A, C, and E vitamins, folic acid, calcium, and selenium. Carotene and lutein are present in berries as well as phytosterols such as sitosterol and stigmasterol and also contain triterpene esters, and there is an excellent source of phenolic molecules such as flavonols, flavanols, proanthocyanidins, ellagitannins, phenolic acids, and anthocyanins specially cyanidin-3-glucoside, gallic acid, pelargonidin, delphinidin, peonidin, and malvidin, among others [22].

The metabolism, bioavailability, and biological effects attributed to berries depend specifically on the type of chemical structure contained in its phenolic compounds that individually or synergistically exert protection against several health disorders [23]. **Table 2** shows the main phytochemical compounds present in berries and their representative chemical structures.


Raspberry Black Red (FW) 267 234.25 197.2 ± 3.5 68.17 ± 3.02 Cyanidin 3-glucoside [25] Blackcurrant (DW) 2382.4 ± 60.8 403.3 ± 11 Cyanidin 3-rutinoside [26]

*Chemical structure was determined according to berry bioactive compound. TP: total polyphenols; TF: total flavonoids; TA: total anthocyanins; FW: fresh weight; DW: dry weight.*

#### **Table 2.**

*Total polyphenols, anthocyanins and characteristic structure content of berries.*

#### **3.1 Polyphenols**

Polyphenols or phenolic compounds are phytochemicals that result from the secondary metabolism of plants coming from the metabolic pathway of shikimic acid and acetate-malonate. They are composed of various chemical structures characterized by an aromatic nucleus of benzene substituted by a hydroxyl group called phenol [21]. Differences between subclasses are given by the number of phenolic rings and the elements attached to them, thus creating several families of compounds, such as flavonoids, anthocyanins, flavones, tannins, and coumarins, among others [21, 27–29].

Polyphenols are present in fruits, vegetables, leaves, nuts, seeds, flowers, and barks [30] and act as inhibitors or activators for a wide variety of mammalian enzyme systems and as metal chelators and oxygen free radical scavengers [31, 32]. Moreover, it has been reported that some flavonoids rise ion chlorine flow at the GABAA receptor in male rats [33, 34]. They can act as positive or negative

**31**

*Berry Supplementation and Their Beneficial Effects on Some Central Nervous System Disorders*

modulators by direct actions on the effect of GABA [35, 36]. Considerable scientific evidence has shown that flavonoids are able to cross into the brain and influence brain function [37, 38]. They have a variety of effects like relief of anxiety, antide-

The ability of polyphenols to modulate the activity of different enzymes and consequently interfere in signaling mechanisms and different cellular processes may be due, in part, to the physicochemical characteristics of these compounds, which allow them to participate in different oxide-reduction cellular metabolic reactions [40]. A diet rich in polyphenols has been shown to augment health [41]. It is best known for its biological effects in humans as anti-inflammatory [42] and anticarcinogenic [43]; in vitro as antiviral [44]; and in animals as gastroprotector [45] and antibacterial [46]; among others. More than 8000 phenolic compounds are known in nature [47], which according to their chemical composition are divided into 2 groups: phenolic acids (benzoic and cinnamic) and flavonoids (flavonoids, anthocyanins, and tannins) [48]. For the purposes of this chapter, we will focus on describing flavonoids in a general sense and anthocyanins in a particular manner.

Their name derives from the Latin *flavus*, which means "yellow," and constitutes

The main subgroups of flavonoid include flavonols, flavones, flavanones (dihydroflavones), isoflavones, and anthocyanins [50]. The flavonoid quercetin (4 mg/day) produces antineoplastic effects [51] and cholesterol-lowering effects in Japanese women aged 29–79 years old (9.3 ± 7.4 mg/day) [52], and at preclinical research in rats, quercetin (25 and 50 mg/kg) produces antithrombotic effects [53], while a hepatic regenerative effect was detected with supplementations of silymarin (100 mg/kg/day) [54]. Among the most reported effects of flavonoids on the central nervous system are their participation in learning and memory mechanisms in Sprague Dawley rats supplemented with nobiletin (725 mg; extracted from *Citrus depressa* peels) [55]; in vitro aid in the treatment of AD by inhibiting the formation of plaques related to memory loss (myricetin, 1 mM) [56] and their neuroprotective role in PD (quercetin, 0.1 μM, or sesamin, 1 pM) [57]; and in male Swiss mice, antidepressant effect supplemented with *Schinus molle* L. (0.3–3 mg/kg) [58] and anxiolytic activities in Wistar rats (1 mg/kg of chrysin i.p.) and zebra fish (1 98 μL/0.1 g b.w.) [59].

Anthocyanins are an important group of water-soluble flavonoid compounds responsible for the red, purple, and blue colors in flowers, fruits, and other parts of plants that are not toxic for human consumption [48]. Their name derives from the Greek *ανθό*ς (*anthos*) meaning "flower" and *κυανό*ς (*kyáneos*) meaning "blue" [60]. They are polyhydroxy- or polymethoxy-glycosides derived from the basic structure, 2-phenyl benzopyryllium [61]. They consist of structures known as anthocyanidins or aglycones, which consist of an aromatic ring attached to a heterocyclic ring containing oxygen which, in turn, is linked to a third aromatic ring. When anthocyanidins are found in glucosylated form, they are then known as anthocyanins and are mainly accompanied by glucose, rhamnose, galactose, arabinose, xylose, and other disaccharides and trisaccharides [62]. These carbohydrates are

the most abundant subclass of polyphenols within the vegetable kingdom [49]. They are low molecular weight compounds sharing a common diphenylpyrane skeleton (C6-C3-C6′), composed by two phenyl rings (A and B) bound through a heterocyclic pyran C ring. All flavonoids are hydroxylated structures in their

aromatic rings and are therefore polyphenolic structures [41].

pressant actions, and neuroprotective [29] and sedative actions [39].

*DOI: http://dx.doi.org/10.5772/intechopen.90428*

**3.2 Flavonoids**

**3.3 Anthocyanins**

#### *Berry Supplementation and Their Beneficial Effects on Some Central Nervous System Disorders DOI: http://dx.doi.org/10.5772/intechopen.90428*

modulators by direct actions on the effect of GABA [35, 36]. Considerable scientific evidence has shown that flavonoids are able to cross into the brain and influence brain function [37, 38]. They have a variety of effects like relief of anxiety, antidepressant actions, and neuroprotective [29] and sedative actions [39].

The ability of polyphenols to modulate the activity of different enzymes and consequently interfere in signaling mechanisms and different cellular processes may be due, in part, to the physicochemical characteristics of these compounds, which allow them to participate in different oxide-reduction cellular metabolic reactions [40].

A diet rich in polyphenols has been shown to augment health [41]. It is best known for its biological effects in humans as anti-inflammatory [42] and anticarcinogenic [43]; in vitro as antiviral [44]; and in animals as gastroprotector [45] and antibacterial [46]; among others. More than 8000 phenolic compounds are known in nature [47], which according to their chemical composition are divided into 2 groups: phenolic acids (benzoic and cinnamic) and flavonoids (flavonoids, anthocyanins, and tannins) [48]. For the purposes of this chapter, we will focus on describing flavonoids in a general sense and anthocyanins in a particular manner.

#### **3.2 Flavonoids**

*Behavioral Pharmacology - From Basic to Clinical Research*

267 234.25

*TA: total anthocyanins; FW: fresh weight; DW: dry weight.*

*Total polyphenols, anthocyanins and characteristic structure content of berries.*

**Berry TP mg/100 g TA mg/100 g Characteristic** 

Blueberry (FW) 711.3 ± 360 ± 0.76 Gallic acid [22]

197.2 ± 3.5 68.17 ± 3.02 **structure**

Cyanidin 3-glucoside [25]

2611 104 Gallic acid [23]

59 117 Cyanidin 3-glucoside [24]

2382.4 ± 60.8 403.3 ± 11 Cyanidin 3-rutinoside [26]

**Ref**

**30**

**3.1 Polyphenols**

**Table 2.**

Blackberry (FW)

Cranberry (DW)

Raspberry Black Red (FW)

Blackcurrant (DW)

Polyphenols or phenolic compounds are phytochemicals that result from the secondary metabolism of plants coming from the metabolic pathway of shikimic acid and acetate-malonate. They are composed of various chemical structures characterized by an aromatic nucleus of benzene substituted by a hydroxyl group called phenol [21]. Differences between subclasses are given by the number of phenolic rings and the elements attached to them, thus creating several families of compounds, such as flavonoids, anthocyanins, flavones, tannins, and coumarins, among others [21, 27–29]. Polyphenols are present in fruits, vegetables, leaves, nuts, seeds, flowers, and barks [30] and act as inhibitors or activators for a wide variety of mammalian enzyme systems and as metal chelators and oxygen free radical scavengers [31, 32]. Moreover, it has been reported that some flavonoids rise ion chlorine flow at the GABAA receptor in male rats [33, 34]. They can act as positive or negative

*Chemical structure was determined according to berry bioactive compound. TP: total polyphenols; TF: total flavonoids;* 

Their name derives from the Latin *flavus*, which means "yellow," and constitutes the most abundant subclass of polyphenols within the vegetable kingdom [49]. They are low molecular weight compounds sharing a common diphenylpyrane skeleton (C6-C3-C6′), composed by two phenyl rings (A and B) bound through a heterocyclic pyran C ring. All flavonoids are hydroxylated structures in their aromatic rings and are therefore polyphenolic structures [41].

The main subgroups of flavonoid include flavonols, flavones, flavanones (dihydroflavones), isoflavones, and anthocyanins [50]. The flavonoid quercetin (4 mg/day) produces antineoplastic effects [51] and cholesterol-lowering effects in Japanese women aged 29–79 years old (9.3 ± 7.4 mg/day) [52], and at preclinical research in rats, quercetin (25 and 50 mg/kg) produces antithrombotic effects [53], while a hepatic regenerative effect was detected with supplementations of silymarin (100 mg/kg/day) [54].

Among the most reported effects of flavonoids on the central nervous system are their participation in learning and memory mechanisms in Sprague Dawley rats supplemented with nobiletin (725 mg; extracted from *Citrus depressa* peels) [55]; in vitro aid in the treatment of AD by inhibiting the formation of plaques related to memory loss (myricetin, 1 mM) [56] and their neuroprotective role in PD (quercetin, 0.1 μM, or sesamin, 1 pM) [57]; and in male Swiss mice, antidepressant effect supplemented with *Schinus molle* L. (0.3–3 mg/kg) [58] and anxiolytic activities in Wistar rats (1 mg/kg of chrysin i.p.) and zebra fish (1 98 μL/0.1 g b.w.) [59].

#### **3.3 Anthocyanins**

Anthocyanins are an important group of water-soluble flavonoid compounds responsible for the red, purple, and blue colors in flowers, fruits, and other parts of plants that are not toxic for human consumption [48]. Their name derives from the Greek *ανθό*ς (*anthos*) meaning "flower" and *κυανό*ς (*kyáneos*) meaning "blue" [60].

They are polyhydroxy- or polymethoxy-glycosides derived from the basic structure, 2-phenyl benzopyryllium [61]. They consist of structures known as anthocyanidins or aglycones, which consist of an aromatic ring attached to a heterocyclic ring containing oxygen which, in turn, is linked to a third aromatic ring. When anthocyanidins are found in glucosylated form, they are then known as anthocyanins and are mainly accompanied by glucose, rhamnose, galactose, arabinose, xylose, and other disaccharides and trisaccharides [62]. These carbohydrates are

always bound to anthocyanidin position 3, and glucose is often found additionally in position 5 and, less commonly, in positions 7, 3′, and 4′ [63].

Anthocyanins are less water-soluble than when they are found in glucosinolates and rarely exist in free form in food. Today, about 19 natural anthocyanidins are known, although the most commonly found in foods are six: pelargonidin, delphinidin, cyanidin, petunidin, peonidin, and malvidin [64], names derived from the plant source from which they were first isolated. In the same sense, a measure of the antioxidant capacity of anthocyanin pigments revealed that cyanidin-3-glucoside and delphinidin-3-glucoside have the highest antioxidant activity [65] and have been identified in fruits coming from the berry family [66], specifically in blackberries [67, 68].

It is important to mention that anthocyanins resist passage through the digestive tract of mammals and are absorbed in the stomach and in the middle portion of the small intestine, reaching the bloodstream almost intact [69]; they reach organs such as the liver, eyes, and brain, thus accumulating in them [14, 70].

#### **4. Biological effects**

The biological functions of anthocyanins can be classified into two types: those related to their antioxidant capacity and those involved in the modulation of cell signaling pathways [71]. In general, they are attributed with effects such as the prevention and/or reduction of atherosclerosis [72]; reduction in the incidence of cardiovascular disease [73]; anticancer [74] and anti-inflammatory activity [75]; hypoglycemic effects [76]; and augmented visual acuity [77] and cognition [78].

Specifically, anthocyanins cross the blood-brain barrier and accumulate in brain regions related to learning and memory, such as the hippocampus and cerebral cortex, modifying behavior [2]. It has been observed in in vitro studies that consumption of these compounds inhibits the enzyme monoamine oxidase (MAO), in which increased activity is related to AD and other neurological disorders [79]. In addition, they display antioxidant capabilities, such as decreasing free radicals and stress signals controlling calcium homeostasis in the brain [80, 81], as well as the presence of hydrogen peroxide (H2O2) and radicals peroxide (ROO) and superoxide (O2) [82, 83]. They also exert protective effects against oxidative stress in cellular models of PD [84] and promote optimal neurotransmission, primarily in advanced age [21].

It has also been observed that anthocyanins ameliorate anti-ocular-inflammatory in male Lewis rats supplemented with crude aronia extract (*Aronia melanocarpa*) in doses of 100 mg/kg, an effect similar to that found in ophthalmic prednisolone in a dose of 10 mg; this effect is evidenced by the direct blockage of the expression of the iNOS and COX-2 enzymes leading to suppression of NO, PGE2, and TNF-α production [85]. Another study in female Wistar rats ovariectomized and supplemented with anthocyanin (200 mg/kg, 7 days of treatment) showed an augment in learning and memory in rats with estrogen deficiency caused by ovariectomy, showing lower errors and latency times in shuttle box test [86].

#### **5. Berries and bioactive compounds on brain diseases**

The recent increase in life expectancy worldwide has augmented the incidence of age-related diseases, particularly neurodegenerative diseases and psychiatric disorders.

Below, we will describe the effects of berry consumption and the relationship between diseases such as anxiety, depression, Alzheimer's and Pasrkinson's diseases, as well as human cognition, because those are the most common mental illness and neurodegenerative diseases [5].

**33**

*Berry Supplementation and Their Beneficial Effects on Some Central Nervous System Disorders*

In addition, you will find in **Table 3** the most recent research carried out related with supplementation in humans and in animal models and, additionally, study

Anxiety is a common and chronic psychiatric disorder that is a source of suffering and impairment [96]. In 2017, the World Health Organization reported that more than 260 million people suffer from an anxiety disorder [97]. Its pharmacological treatment is based on the use of benzodiazepine drugs, as well as some antidepressants with anxiolytic activity [98]. Unfortunately, these drugs are accompanied by severe side effects such as sedation, pharmacological tolerance, and drug dependence [99, 100]; in this sense, some patients complement their therapies

The study of the potential effect of berries on anxiety, due to their high content of polyphenols and anthocyanins associated with anxiolytic activity at the preclinical level, has attracted important interest [101, 102]. It has been observed that these compounds, present in blueberries, have shown anxiolytic effects in animal models and their possible mechanisms of action are related to the antioxidant properties of anthocyanins [103] which inhibit the enzyme monoamine oxidases (MAOs),

Supplementation with blueberries in mice for 30 days has shown to increase the time spent in the open arms (anxiolytic effect) in the elevated plus maze test (EPM); in addition, it is shown to reduce oxidative damage to neural DNA, and this antioxidant neural protection has been proposed as a mechanism for the anxiolytic property of berries [19]. One of the most studied berries for anxiety at the preclinical level is the black

chokeberry (*Aronia melanocarpa)* belonging to the Rosacea family [105], for example, in male Wistar rats, the acute administration of the juice at doses of 5 and 10 ml/kg exerts dose-dependent anxiolytic activity in the social interaction test in a manner comparable to diazepam [102]. While, subchronic administration of *Aronia melanocarpa* fruit juice (10 ml/kg, orally) in male Wistar rats induces a time-dependent anxiolytic effect [106]. Furthermore, the month-long unlimited consumption of black chokeberry juice (>20 ml/kg b.w daily) exerts reduction of anxiety-like behavior associated with MAO-A/MAO-B inhibitions [104], which is probably due to the high antioxidant activity that black chokeberry has shown to have [107]. On the other hand, this berry fruit has been evaluated in different concentrations and behavioral tests such as the EPM and the social interaction test [102]. Likewise, a methanolic extract of blackberry (*Rubus fruticosus*) was used and reported an anxiolytic effect (100, 200, and 300 mg/kg, orally) in the hole-board test in a dose-dependent response [108]; also, the effect of *Rubus brasiliensis* fruits in Wistar rats has been studied, reporting an anxiolytic effect in EPM, in a dose of 2.5 mg/kg administered per gavage [109]. In turn, an anxiety-related effect has been reported in treated male Swiss mice through supplemented water (2.6–3.2 mg/kg)

per day of anthocyanins present in blueberry (*Vaccinium ashei*) [19].

Our working group [4] recently reported the anxiolytic effect from blackberry juice (doses intermediate: 5.83 mg/kg anthocyanins, 27.10 mg/kg polyphenols) on EPM in male Wistar rats, and the design was accompanied by the forced swim test (6 min). A decrease in the anxiety index was observed, without alterations in locomotor activity. This was similar to the group administered with the anxiolytic drug diazepam. Results revealed a better response to behavioral stress in the rats treated with blackberry juice, reinforcing the effects previously reported in EPM (**Table 3**). The anxiolytic effect of some flavonoids and anthocyanins has been identified by affinity to GABAA receptors [89, 110]. However, its antioxidant capacity is still

*DOI: http://dx.doi.org/10.5772/intechopen.90428*

with natural compounds coming from plants.

decreasing its activity and providing neuroprotection [77, 104].

design and summarized findings.

**5.1 Anxiety**

In addition, you will find in **Table 3** the most recent research carried out related with supplementation in humans and in animal models and, additionally, study design and summarized findings.

#### **5.1 Anxiety**

*Behavioral Pharmacology - From Basic to Clinical Research*

in position 5 and, less commonly, in positions 7, 3′, and 4′ [63].

coming from the berry family [66], specifically in blackberries [67, 68].

as the liver, eyes, and brain, thus accumulating in them [14, 70].

**4. Biological effects**

always bound to anthocyanidin position 3, and glucose is often found additionally

Anthocyanins are less water-soluble than when they are found in glucosinolates and rarely exist in free form in food. Today, about 19 natural anthocyanidins are known, although the most commonly found in foods are six: pelargonidin, delphinidin, cyanidin, petunidin, peonidin, and malvidin [64], names derived from the plant source from which they were first isolated. In the same sense, a measure of the antioxidant capacity of anthocyanin pigments revealed that cyanidin-3-glucoside and delphinidin-3-glucoside have the highest antioxidant activity [65] and have been identified in fruits

It is important to mention that anthocyanins resist passage through the digestive tract of mammals and are absorbed in the stomach and in the middle portion of the small intestine, reaching the bloodstream almost intact [69]; they reach organs such

The biological functions of anthocyanins can be classified into two types: those related to their antioxidant capacity and those involved in the modulation of cell signaling pathways [71]. In general, they are attributed with effects such as the prevention and/or reduction of atherosclerosis [72]; reduction in the incidence of cardiovascular disease [73]; anticancer [74] and anti-inflammatory activity [75]; hypoglycemic effects [76]; and augmented visual acuity [77] and cognition [78]. Specifically, anthocyanins cross the blood-brain barrier and accumulate in brain

regions related to learning and memory, such as the hippocampus and cerebral cortex, modifying behavior [2]. It has been observed in in vitro studies that consumption of these compounds inhibits the enzyme monoamine oxidase (MAO), in which increased activity is related to AD and other neurological disorders [79]. In addition, they display antioxidant capabilities, such as decreasing free radicals and stress signals controlling calcium homeostasis in the brain [80, 81], as well as the presence of hydrogen peroxide (H2O2) and radicals peroxide (ROO) and superoxide (O2) [82, 83]. They also exert protective effects against oxidative stress in cellular models of PD [84]

and promote optimal neurotransmission, primarily in advanced age [21].

**5. Berries and bioactive compounds on brain diseases**

It has also been observed that anthocyanins ameliorate anti-ocular-inflammatory in male Lewis rats supplemented with crude aronia extract (*Aronia melanocarpa*) in doses of 100 mg/kg, an effect similar to that found in ophthalmic prednisolone in a dose of 10 mg; this effect is evidenced by the direct blockage of the expression of the iNOS and COX-2 enzymes leading to suppression of NO, PGE2, and TNF-α production [85]. Another study in female Wistar rats ovariectomized and supplemented with anthocyanin (200 mg/kg, 7 days of treatment) showed an augment in learning and memory in rats with estrogen deficiency caused by ovariectomy, showing lower errors and latency times in shuttle box test [86].

The recent increase in life expectancy worldwide has augmented the incidence of age-related diseases, particularly neurodegenerative diseases and psychiatric disorders. Below, we will describe the effects of berry consumption and the relationship between diseases such as anxiety, depression, Alzheimer's and Pasrkinson's diseases, as well as human cognition, because those are the most common mental illness and

**32**

neurodegenerative diseases [5].

Anxiety is a common and chronic psychiatric disorder that is a source of suffering and impairment [96]. In 2017, the World Health Organization reported that more than 260 million people suffer from an anxiety disorder [97]. Its pharmacological treatment is based on the use of benzodiazepine drugs, as well as some antidepressants with anxiolytic activity [98]. Unfortunately, these drugs are accompanied by severe side effects such as sedation, pharmacological tolerance, and drug dependence [99, 100]; in this sense, some patients complement their therapies with natural compounds coming from plants.

The study of the potential effect of berries on anxiety, due to their high content of polyphenols and anthocyanins associated with anxiolytic activity at the preclinical level, has attracted important interest [101, 102]. It has been observed that these compounds, present in blueberries, have shown anxiolytic effects in animal models and their possible mechanisms of action are related to the antioxidant properties of anthocyanins [103] which inhibit the enzyme monoamine oxidases (MAOs), decreasing its activity and providing neuroprotection [77, 104].

Supplementation with blueberries in mice for 30 days has shown to increase the time spent in the open arms (anxiolytic effect) in the elevated plus maze test (EPM); in addition, it is shown to reduce oxidative damage to neural DNA, and this antioxidant neural protection has been proposed as a mechanism for the anxiolytic property of berries [19].

One of the most studied berries for anxiety at the preclinical level is the black chokeberry (*Aronia melanocarpa)* belonging to the Rosacea family [105], for example, in male Wistar rats, the acute administration of the juice at doses of 5 and 10 ml/kg exerts dose-dependent anxiolytic activity in the social interaction test in a manner comparable to diazepam [102]. While, subchronic administration of *Aronia melanocarpa* fruit juice (10 ml/kg, orally) in male Wistar rats induces a time-dependent anxiolytic effect [106]. Furthermore, the month-long unlimited consumption of black chokeberry juice (>20 ml/kg b.w daily) exerts reduction of anxiety-like behavior associated with MAO-A/MAO-B inhibitions [104], which is probably due to the high antioxidant activity that black chokeberry has shown to have [107].

On the other hand, this berry fruit has been evaluated in different concentrations and behavioral tests such as the EPM and the social interaction test [102]. Likewise, a methanolic extract of blackberry (*Rubus fruticosus*) was used and reported an anxiolytic effect (100, 200, and 300 mg/kg, orally) in the hole-board test in a dose-dependent response [108]; also, the effect of *Rubus brasiliensis* fruits in Wistar rats has been studied, reporting an anxiolytic effect in EPM, in a dose of 2.5 mg/kg administered per gavage [109]. In turn, an anxiety-related effect has been reported in treated male Swiss mice through supplemented water (2.6–3.2 mg/kg) per day of anthocyanins present in blueberry (*Vaccinium ashei*) [19].

Our working group [4] recently reported the anxiolytic effect from blackberry juice (doses intermediate: 5.83 mg/kg anthocyanins, 27.10 mg/kg polyphenols) on EPM in male Wistar rats, and the design was accompanied by the forced swim test (6 min). A decrease in the anxiety index was observed, without alterations in locomotor activity. This was similar to the group administered with the anxiolytic drug diazepam. Results revealed a better response to behavioral stress in the rats treated with blackberry juice, reinforcing the effects previously reported in EPM (**Table 3**).

The anxiolytic effect of some flavonoids and anthocyanins has been identified by affinity to GABAA receptors [89, 110]. However, its antioxidant capacity is still


**35**

**Topic** Alzheimer's disease

Gutierres *et al*., 2014 [89]/Brazil

Male Wistar rats (3-months-1-year-old, 350-400g), 7 days of treatment with 200 mg/kg anthocyanin (ANT) the rats were injected with intracerebroventricular streptozotocin (3 mg/kg) (STZ), and four days later the behavior parameters were performed.

McNamara *et al*, 2018 [90]/USA

Parkinson's

Fan *et al*.,

n= 11 male patients with Parkinson's

disease and older than 40 years old.

2 sessions where samples of plasma

and cerebrospinal fluid (CSF) were

taken (in both sessions a 12-hour low

anthocyanin diet was requested before

taking the samples).

Qian *et al*.,

n=45, 3 weeks treatment, 6-week old

Five groups were used: 1) control (received i.p. saline), 2) MPTP

(received i.p. MPTP 30 mg/kg for 5 days and saline, 3)BBE 50 mg/

kg (received i.p. MPTP 30 mg/kg for 5 days and 50 mg/kg blueberry

extract (BBE), 4) BBE 100 mg/kg (received i.p. MPTP 30 mg/kg for

5 days and 100 mg/kg of BBE) and 5) i.p MPTP and fed daily with

levodopa and benserazide (10 mg/kg/day).

male C57BL/6 mice (18-22 g). This

study was designed to investigate the

effects of the ANC rich blueberry

extracts (BBE) on behavior and

oxidative stress in the mouse model

of PD induced by 1- methyl-4-

phenyl-1,2,3,6- tetrahydropyridine

(MPTP).

2019 [92]/

China

2018 [91]/

New

Zealand

Disease

n=76, 24 weeks treatment, study conducted in men and women aged 62-80 with cognitive impairment. They used the Dysexecutive Questionnaire.

**Author/ location**

**Study design**

**Intervention** Four different groups: control (CTRL), anthocyanin (ANT), streptozotocin (STZ) and streptozotocin + anthocyanin (STZ + ANT).

A memory deficit was found in the STZ group, but ANT treatment showed that it prevents this impairment of memory. This work demonstrated that anthocyanin is able to regulate ion pump activity and cholinergic neurotransmission, as well as being able to enhance memory and act as an anxiolytic compound in animals with sporadic dementia of Alzheimer's type.

**Summarized findings**

*Berry Supplementation and Their Beneficial Effects on Some Central Nervous System Disorders*

*DOI: http://dx.doi.org/10.5772/intechopen.90428*

It was demonstrated that supplementation with FO and BB

showed a reduction of self-reported inefficiencies in daily

operation, by the BB group showed less interference in memory.

The neuropeptide cyclic glycine protein (cGP), a natural BCA

nutrient, was shown to be effectively absorbed in the brain after

supplementation. The increase of cyclic glycine proline (cGP) in

plasma and cephalorachidian fluid in Parkison patients is mainly

due to central uptake of the neuropeptide in plasma. Thus, the

role of insulin-like growth factor 1 (IGF-1) improves in patients

BBE improved motor function in MPTP- induced Parkinson's

mice through a possible mechanism of their antioxidant

capacity to eliminate free radicals and reduce oxidative damage

to neurons.

with Parkinson's disease.

Four groups were used: FO (fish oil + placebo powder), BB (blueberry

[*Vaccinium sp*] powder + placebo oil), FO+BB (fish oil + cranberry

powder), PL (oil + placebo powder). Fish oil (400 mg EPA (1.6 g) and

200 mg DHA (0.8 g)) and cranberry powder (phenolic concentration

(20.4±0.31), anthocyanins (14.5±0.04)).

Study of pre and post treatment samples, where patients were

supplemented with 300 mg blackcurrant capsules (35% anthocyanins,

Super Currantex® 20) twice daily for four weeks.


*Berry Supplementation and Their Beneficial Effects on Some Central Nervous System Disorders DOI: http://dx.doi.org/10.5772/intechopen.90428*

*Behavioral Pharmacology - From Basic to Clinical Research*

**34**

**Topic**

**Author/**

**Study design**

**Intervention**

**Summarized findings**

The intermediate dose of blackberry juice (5.83 mg/kg of

anthocyanins, 27.10 mg / kg of polyphenols) had an anxiolytic

effect similar to DZP, improving coping strategies at the

behavioral level. These results were supplemented by the forced

swim test, where medium and high doses improved the response

to acute stress.

Higher flavonoid intakes may be associated with lower

depression risk, particularly among older women.

**location**

Anxiety

Fernández-Demeneghi

n=45, 21 days treatment, Wistar male

Five groups were used: Veh (control group administered with 8.7 ml/kg), BL

(low dose group of blackberry juice, 2.6 mg/kg of anthocyanins, 14.57 mg/

kg of polyphenols) BM (medium dose group of blackberry juice, 5.83 mg/

kg anthocyanins, 27.10 mg/kg polyphenols) BH (high-dose blackberry juice

group 10.57 mg/kg anthocyanins, 38.4 mg/kg polyphenols) DZP (diazepam

Two samples were used: Nurses' Health Study (NHSI) (from 1976 nurses

aged 30-55) and NHSII (from 1989 nurses aged 25-42).

group administered 2 mg/kg).

rats (200- 250 g)

*et al*.,

2019 [4]/

Mexico

Depression

Chang

n=82643 women. Prospectively, the

study examined the associations between

the estimated usual intake of flavonoids

in the diet and the risk of depression.

Semiquantitative food frequency

questionnaire was applied (FFQ).

n=21 university students (18-21 years)/

Two groups were used: The flavonoid-rich wild blueberry (WBB),

In both studies, an increase in positive affection was observed

after 2 hours of consumption of the WBB drink. Flavonoid

supplementation can play a key role in promoting positive mood

and are a possible way to prevent dysphoria and depression.

which administered 253 mg of anthocyanins, a combination of 30 g of

lyophilized WBB, 30 ml of Rocks Orange Squash and 220 ml of water),

placebo (4 mg of WBB, 30 ml of Rocks Orange Squash and 220 ml of

Two groups were used: The flavonoid-rich wild blueberry (WBB) 253 mg

anthocyanins, combination of 30 g lyophilized WBB, 30 ml Rocks Orange

Squash and 170 ml water); placebo (4 mg WBB, 30 ml Rocks Orange

Squash and 170 ml water were combined).

Four groups were used: control (healthy group), BCCAO (group with

The protective effects of WE in post-stroke depression in

a mouse model were demonstrated *in vivo*, both groups

administered with WE reduced immobility time in forced swim

and tail suspension tests. These findings are correlated with the

antioxidant capacity of its bioactive constituents.

The results showed that the antidepressant-like activity provided

by the extract, which was found to restore normal mouse behavior

in both despair swimming and tail suspension tests, could be

linked to its antioxidant activity, leading to the conclusion that

maqui berries might be useful for supporting pharmacological

therapy of Post-stroke depression by modulating oxidative stress.

bilateral occlusion of the common carotid artery) 10 mg/kg (group with

lesion + 10 mg/kg of aqueous extract of red berries of *H. Androsaemum*

(WE) 30 mg/kg (group with lesion + 30 mg/kg of WE).

Five groups were used: 1) control: healthy group, 2) BCCAO (group with

stroke common carotid artery bilateral occlusion), 3) 25 mg/kg (lesion +

25 mg/kg Maqui berry extract (MBE)), 4) 50 mg/kg (lesion + 50 mg/kg

MBE), 5) 100 mg/kg (lesion + 100 mg/kg MBE).

water were combined).

The Positive and Negative Affect

Schedule-NOW (PANAS-NOW) was

used to assess current mood.

n=50 children (7-10)/child version of

the Positive and Negative Affect Scale

(PANAS-C).

Nabavi

n=40, 7 days treatment, balb/c strain

mice (5 weeks old, 20-25 g).

*et al*., 2018

[87]/Iran

Di Lorenzo

n=50, 7 days treatment i.p., balb/c

strain mice (2 weeks old, 20-25 g).

*et al*, 2019

[88]/Italy

Khalid

*et al*., 2017

[86]/United

Kingdom

*et al*.,

2016 [85]/

USA-UK


**Table 3.** *Recent research in humans and animal models related to supplementation with berries.*

**37**

*Berry Supplementation and Their Beneficial Effects on Some Central Nervous System Disorders*

considered the main mechanism of action [106], since oxidative stress has been

Depression is the most prevalent psychiatric disorder; according to the World Health Organization, it affects 300 million people worldwide [97]. Depressive disorders are characterized by the presence of a sad and irritable mood accompanied by somatic and cognitive changes that negatively impact everyday life function [97] and result in high financial costs [111]. A great variety of drugs exist for its treatment [112], in which therapeutic effects are driven by actions on diverse neurotransmission systems (serotonergic, dopaminergic, and noradrenergic), exerting long-term changes which can restore neuronal function, for example, restoration of basal levels of neurotransmitters mainly serotonin, increase in neurotrophic factors (brain-derived neurotrophic factor and nerve growth factor) that can indirectly modify neuronal microarchitecture, reduction of oxidative stress, as well as neuroinflammation processes in structures related to the pathophysiology of depression which can impact at the affective level exerting favorable effects on the quality of life of the subjects. These drugs include tricyclic antidepressants (i.e., imipramine), selective serotonin recapture inhibitors (i.e., fluoxetine), monoamine oxidase inhibitors (phenelzine), and dual antidrepressant drugs (venlafaxine), among others [113]. Most of these drugs have a late onset and are often accompanied by side effects when taken for prolonged periods. This has encouraged a search for new substances with potential antidepressant effects and, most importantly, the use of

An association between the role the hippocampus and the etiology of depression has been suggested, given that a reduction in hippocampal neurogenesis has been observed in depressed patients with respect to the non-depressed control group, which is accompanied by a decrease in the hippocampal volume [114]. In this sense, antidepressants such as fluoxetine have been shown to ameliorate neurogenesis in

At the preclinical level, the administration of *Aronia melanocarpa* juice showed a decrease in total immobility time in the forced swimming test [107], similar to animals treated with imipramine. In addition, the study was supplemented with in vitro testing, where inhibition of the enzyme monoamine oxidase was observed, both in its A form and to a lesser extent in its B form [104]. MAO-A and MAO-B inhibitors are used clinically for the treatment of psychiatric and neurological disorders, respectively [116]. This activity has been proposed as another mechanism for the action of berries in mental disorders, as it is related to increased levels of

In addition, human studies related to blueberry and red berry supplementation have shown that a higher intake of these foods is associated with a lower risk of depression [85, 86]. Similarly, studies in mice have shown similar effects with the consumption of red berries, observing a reduction in depressive-like behaviors [87, 88] (**Table 3**).

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive memory loss, as well as cognitive decline [117] in which prevalence augments with age [118]. The neuropathologic changes underlying AD include senile plaques formed by the peptide β-amyloid and neurofibrillary tangles composed of hyperphosphorylated Tau protein that promotes synaptic dysfunction and neuronal

proposed as an important contributor to anxiety generation [79].

*DOI: http://dx.doi.org/10.5772/intechopen.90428*

**5.2 Depression**

possible natural alternatives.

the hippocampus [115].

**5.3 Alzheimer's disease**

death early and consistently [119].

serotonin, dopamine, and noradrenaline.

considered the main mechanism of action [106], since oxidative stress has been proposed as an important contributor to anxiety generation [79].
