**5.2 Depression**

*Behavioral Pharmacology - From Basic to Clinical Research*

It was demonstrated that the consumption of drinks

supplemented with blackcurrants produce a cognitive benefit

in healthy young people, evidenced by greater accuracy in the

RIVP test; likewise, Blackadder improved reaction times in

the task of monitoring digits. Clinically significant inhibition

of monoamine oxidase-B and monoamine oxidase-A was

identified using a commonly consumed fruit.

It was identified that anthocyanins (143 mg) present in

blueberry juice have memory benefits in children aged 8 to

10 years, however, little evidence in attention, visuospatial,

working memory were observed.

**36**

**Topic** Other

Devore

n=16,010 women, aged ≥70; follow-up

Follow-up questionnaire on eating habits (2-year period) and

assessment of congenital impairment. Six cognitive tests were

administered: Telephone Interview of Cognitive Status, a telephone

adaptation of the Mini-Mental State Examination; East Boston Memory

Test – immediate and delayed recalls; category fluency; delayed recall

of the Telephone Interview of Cognitive Status 10- word list; and

Three intervention drinks were used: 1. control (containing 0 mg

polyphenols), 2. Blackadder (7.78 mg/kg anthocyanins from an extract

of Ribes nigrum). 3. DelCyan (trademark) (8.05 mg/kg anthocyanins

from a blackcurrant extract).

backwards digit span.

Watson

n=36 healthy, young participants

(18-35 years). The battery used was

formed: digit vigilance, stroop, rapid

visual information processing (RVIP)

and logical reasoning.

*et al*., 2015

[94]/New

Zealand

Whyte &

n=16 children (8-10 years), 7 days

Two intervention drinks were used: 1. blueberry (prepared by mixing

200 g of Star variety blueberries with 100 ml, which contained 143 mg

of anthocyanins). Control (combined with blueberry drink for sugars

and vitamin C by adding 0.02 g of vitamin C powder, 8.22 g of sucrose,

9.76 g of glucose and 9.94 g of fructose to 100 ml of semi-skimmed

of treatment. Two hours after

consumption, the children completed

a battery of five cognitive tests

comprising the Go-NoGo, Stroop, Rey's

Auditory Verbal Learning Task, Object

milk).

Location Task, and a Visual N-back.

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

**Table 3.**

Williams

(2015)

[95]/United

Kingdom

assessments were conducted twice, at

effects

*et al*., 2012

[93]/USA

two-year intervals.

**Author/**

**Study design**

**Intervention**

**Summarized findings**

Increased consumption of berries and anthocyanidins, as well

as total flavonoids, was shown to be associated with slower

progression of cognitive impairment in older women.

**location**

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 possible natural alternatives.

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 the hippocampus [115].

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 serotonin, dopamine, and noradrenaline.

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**).

## **5.3 Alzheimer's disease**

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 death early and consistently [119].

Oxidative stress has been associated with the onset and progression of AD [120]. This is supported by the high vulnerability of neurons to reactive oxygen species (ROS) [121]. Oxidative stress can induce damage to membrane lipids, changes in glial and neuronal function, structural damage to DNA, synaptic dysfunction, and apoptosis [122].

Several studies have demonstrated the potential protective effect of blackberry fruits (*Rubus L.* subgenus *Rubus Watson*), in the prevention of age-related neurodegenerative disorders [123], specifically with PD. Berry fruits such as blackberry, black raspberry, blueberry, and strawberry are good sources of phytochemicals that provide protection against neurological disorders [93].

Extracts of black currant have been shown to inhibit the formation and spread of β-amyloid [124] and ROS fibrils. Supplementation of blackberry in in vitro studies has been reported to exhibit potent anti-inflammatory and antiproliferative properties [125, 126]; also, the consumption of blueberries is related to neuronal augment in the hippocampus [5].

Recently a neuroprotective effect of anthocyanins has been observed in a model of AD induced by streptozotocin that resulted in a cognitive deficit (in short-term memory and spatial memory), as well as dysfunction in the activity of the enzyme acetylcholinesterase, while inducing lipid peroxidation and a decrease in antioxidant enzymes in the cerebral cortex [127]. These alterations were attenuated in the group administered with anthocyanins. Similarly, it has been observed that blueberry powder (*Vaccinium* sp.) supplementation in patients with Alzheimer's disease and cognitive decline reduces the self-reported inefficiencies in daily functioning [90] (**Table 3**).

#### **5.4 Parkinson's disease**

Parkinson's disease (PD) is characterized by tremors, stiffness, and akinesia. It is caused by the progressive degeneration of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies. Many Parkinson's risks and preventive factors have been investigated. The onset of this disorder has been associated with exposure to certain pesticides and heavy metals [128], tobacco consumption [129], and coffee consumption [130], among other environmental factors. While current treatments have shown effectiveness in early management of the motor symptoms of the disease [131] and both surgery and deep brain stimulation are useful, PD is currently not yet curable [132]. A diet enriched in phenolic compounds has been shown to have some efficacy in relieving Parkinson's symptoms [133]. Most of the studies related to fruit consumption and disease focus on supplementation with blueberries, strawberries, black currant, and grapes, due to their powerful antioxidant effects related to their high content of polyphenols and anthocyanins [134].

Cell models have reinforced studies of neurodegenerative disorders, recently demonstrating that anthocyanins from grape seed, blueberry, and mulberry enhance mitochondrial function [135] and suppressed dopaminergic cell death caused by rotenone (insecticide and pesticide) in mitochondrial respiration. This has suggested that anthocyanins may alleviate neurodegeneration in PD by improving mitochondrial function. In addition, polyphenols are able to ameliorate inflammatory responses associated with glial activation [136]. Phenolic compounds are known for their ability to eliminate reactive oxygen species (ROS) due to their antioxidant action; however, since their concentrations in the brain are lower than those of endogenous antioxidants, it has begun to be seen that they also exert their neuroprotective effects through additional mechanisms [137, 138], highlighting the inhibition of MAO, in its two forms, A and B [77, 104]. At the preclinical level, one of the most widely used models in PD research is the administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a neurotoxin that causes a severe Parkinson's-like syndrome in humans, monkeys, and mice [139–142]. It has been observed that daily administration of

**39**

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

resveratrol (red wine polyphenol) in male mice C57BL/6 prevented a decrease in striatal dopamine and maintained striatal tyrosine hydroxylase levels. In addition, mice that received resveratrol as pretreatment showed a greater number of immunopositive tyrosine hydroxylase neurons, indicating the protective role of resveratrol over nigral neurons [143]. In the same disease model, it was observed that blueberry extract attenuated behavioral impairment (motor coordination) as well as decreased levels of malondialdehyde in the brains of mice [92]. These data reveal the ability of resveratrol and polyphenols present in blueberry extract to counteract the toxic effects of MPTP administration and in the near future may be used as a complementary neuroprotective therapy (**Table 3**). Current PD therapies act by controlling the disease's symptoms, but do not slow the underlying neurodegeneration in the brains of PD in patients [135]; this is an opportunity to use functional foods as adjuvant therapy in the presence of disease.

Polyphenols present in berries have also been associated with cognitive amelioration and neuronal function, as is the case with grape juice, which in both young [144] and older adults [145] ameliorate neurocognitive functions of memory, attention, and calmness, compared to the placebo group. In this same regard, in mothers (40–50 years) of preadolescent children, an association of grape juice consumption has been observed (≥30 h/week 355 ml, during 12 weeks) with subtle augment in immediate spatial memory and safer driving behavior in a virtual simulator [146]. At the same time, it was found that, in a double-blind crossover design of children (7 and 10 years old), supplementation of 15 or 30 g freeze-dried wild blueberry powder significantly ameliorates word acquisition and recognition, as well as the

In a pilot study in healthy young adults in both genders (18–35 years old), it has been observed that the acute administration of black currant juice (500 mg/day of polyphenols, supplemented only 1 day per week, during 31 days) exerts an anxiolytic-like effect, as well as ameliorates alertness, less fatigue, and reaction speed [94]. In a randomized, double-blind placebo-controlled trial, dietary blueberry of 24 g/day for 3 months raised the cognition in tests of executive function in adults between 60 and 75 years old of both sexes by increasing accuracy during task switching and reduced repetition errors during word-list recall [148]. The positive effects on cognition have been related to activation of the prefrontal cortex using functional magnetic resonance imaging [149]; therefore, the administration of blueberry to have the same effects on these tasks could be exercising greater activation of this structure to raise cognition. Another study found that daily consumption of 6 and 9 ml/kg for 12 weeks of blueberry (*Vaccinium angustifolium* Aiton) juice exerted neurocognitive benefits measured by California Verbal Learning Test-II (CVLT) augmented associate learning and word-list recall in older adults of both sexes who had experienced age-related memory decline [145]. Similarly, randomized controlled trial has shown that dietary berry juice (200 ml/day) for 12 weeks ameliorate memory and cognition in adults (70–80 years old) with cognitive impairment measured using a battery Rey Auditory Verbal Learning Test (RAVLT) [150].

Furthermore, a randomized, double-blind, placebo-controlled study showed that the daily administration of two capsules (10o mg) of a purified extract of blueberry (wild blueberry extract) for 3 months raised episodic and working memory in older adults of both sexes [151]. Additionally, a randomized, singleblind, parallel group design showed that the acute consumption of 200 ml of wild blueberry drink (253 mg anthocyanins) in healthy children aged 7–10 years significantly enhanced the memory and attentional aspects of executive function with respect to the placebo group 2 h after consumption; therefore, the consumption of

ability to overcome the effects of response interference [147].

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

**5.5 Human cognition**

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

resveratrol (red wine polyphenol) in male mice C57BL/6 prevented a decrease in striatal dopamine and maintained striatal tyrosine hydroxylase levels. In addition, mice that received resveratrol as pretreatment showed a greater number of immunopositive tyrosine hydroxylase neurons, indicating the protective role of resveratrol over nigral neurons [143]. In the same disease model, it was observed that blueberry extract attenuated behavioral impairment (motor coordination) as well as decreased levels of malondialdehyde in the brains of mice [92]. These data reveal the ability of resveratrol and polyphenols present in blueberry extract to counteract the toxic effects of MPTP administration and in the near future may be used as a complementary neuroprotective therapy (**Table 3**). Current PD therapies act by controlling the disease's symptoms, but do not slow the underlying neurodegeneration in the brains of PD in patients [135]; this is an opportunity to use functional foods as adjuvant therapy in the presence of disease.

#### **5.5 Human cognition**

*Behavioral Pharmacology - From Basic to Clinical Research*

provide protection against neurological disorders [93].

in the hippocampus [5].

**5.4 Parkinson's disease**

Oxidative stress has been associated with the onset and progression of AD [120]. This is supported by the high vulnerability of neurons to reactive oxygen species (ROS) [121]. Oxidative stress can induce damage to membrane lipids, changes in glial and neuronal function, structural damage to DNA, synaptic dysfunction, and apoptosis [122]. Several studies have demonstrated the potential protective effect of blackberry fruits (*Rubus L.* subgenus *Rubus Watson*), in the prevention of age-related neurodegenerative disorders [123], specifically with PD. Berry fruits such as blackberry, black raspberry, blueberry, and strawberry are good sources of phytochemicals that

Extracts of black currant have been shown to inhibit the formation and spread of β-amyloid [124] and ROS fibrils. Supplementation of blackberry in in vitro studies has been reported to exhibit potent anti-inflammatory and antiproliferative properties [125, 126]; also, the consumption of blueberries is related to neuronal augment

Recently a neuroprotective effect of anthocyanins has been observed in a model of AD induced by streptozotocin that resulted in a cognitive deficit (in short-term memory and spatial memory), as well as dysfunction in the activity of the enzyme acetylcholinesterase, while inducing lipid peroxidation and a decrease in antioxidant enzymes in the cerebral cortex [127]. These alterations were attenuated in the group administered with anthocyanins. Similarly, it has been observed that blueberry powder (*Vaccinium* sp.) supplementation in patients with Alzheimer's disease and cognitive decline reduces the self-reported inefficiencies in daily functioning [90] (**Table 3**).

Parkinson's disease (PD) is characterized by tremors, stiffness, and akinesia. It is caused by the progressive degeneration of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies. Many Parkinson's risks and preventive factors have been investigated. The onset of this disorder has been associated with exposure to certain pesticides and heavy metals [128], tobacco consumption [129], and coffee consumption [130], among other environmental factors. While current treatments have shown effectiveness in early management of the motor symptoms of the disease [131] and both surgery and deep brain stimulation are useful, PD is currently not yet curable [132]. A diet enriched in phenolic compounds has been shown to have some efficacy in relieving Parkinson's symptoms [133]. Most of the studies related to fruit consumption and disease focus on supplementation with blueberries, strawberries, black currant, and grapes, due to their powerful antioxidant effects related to their high content of polyphenols and anthocyanins [134]. Cell models have reinforced studies of neurodegenerative disorders, recently demonstrating that anthocyanins from grape seed, blueberry, and mulberry enhance mitochondrial function [135] and suppressed dopaminergic cell death caused by rotenone (insecticide and pesticide) in mitochondrial respiration. This has suggested that anthocyanins may alleviate neurodegeneration in PD by improving mitochondrial function. In addition, polyphenols are able to ameliorate inflammatory responses associated with glial activation [136]. Phenolic compounds are known for their ability to eliminate reactive oxygen species (ROS) due to their antioxidant action; however, since their concentrations in the brain are lower than those of endogenous antioxidants, it has begun to be seen that they also exert their neuroprotective effects through additional mechanisms [137, 138], highlighting the inhibition of MAO, in its two forms, A and B [77, 104]. At the preclinical level, one of the most widely used models in PD research is the administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a neurotoxin that causes a severe Parkinson's-like syndrome in humans, monkeys, and mice [139–142]. It has been observed that daily administration of

**38**

Polyphenols present in berries have also been associated with cognitive amelioration and neuronal function, as is the case with grape juice, which in both young [144] and older adults [145] ameliorate neurocognitive functions of memory, attention, and calmness, compared to the placebo group. In this same regard, in mothers (40–50 years) of preadolescent children, an association of grape juice consumption has been observed (≥30 h/week 355 ml, during 12 weeks) with subtle augment in immediate spatial memory and safer driving behavior in a virtual simulator [146]. At the same time, it was found that, in a double-blind crossover design of children (7 and 10 years old), supplementation of 15 or 30 g freeze-dried wild blueberry powder significantly ameliorates word acquisition and recognition, as well as the ability to overcome the effects of response interference [147].

In a pilot study in healthy young adults in both genders (18–35 years old), it has been observed that the acute administration of black currant juice (500 mg/day of polyphenols, supplemented only 1 day per week, during 31 days) exerts an anxiolytic-like effect, as well as ameliorates alertness, less fatigue, and reaction speed [94].

In a randomized, double-blind placebo-controlled trial, dietary blueberry of 24 g/day for 3 months raised the cognition in tests of executive function in adults between 60 and 75 years old of both sexes by increasing accuracy during task switching and reduced repetition errors during word-list recall [148]. The positive effects on cognition have been related to activation of the prefrontal cortex using functional magnetic resonance imaging [149]; therefore, the administration of blueberry to have the same effects on these tasks could be exercising greater activation of this structure to raise cognition. Another study found that daily consumption of 6 and 9 ml/kg for 12 weeks of blueberry (*Vaccinium angustifolium* Aiton) juice exerted neurocognitive benefits measured by California Verbal Learning Test-II (CVLT) augmented associate learning and word-list recall in older adults of both sexes who had experienced age-related memory decline [145]. Similarly, randomized controlled trial has shown that dietary berry juice (200 ml/day) for 12 weeks ameliorate memory and cognition in adults (70–80 years old) with cognitive impairment measured using a battery Rey Auditory Verbal Learning Test (RAVLT) [150].

Furthermore, a randomized, double-blind, placebo-controlled study showed that the daily administration of two capsules (10o mg) of a purified extract of blueberry (wild blueberry extract) for 3 months raised episodic and working memory in older adults of both sexes [151]. Additionally, a randomized, singleblind, parallel group design showed that the acute consumption of 200 ml of wild blueberry drink (253 mg anthocyanins) in healthy children aged 7–10 years significantly enhanced the memory and attentional aspects of executive function with respect to the placebo group 2 h after consumption; therefore, the consumption of

the wild blueberry drink during the critical period of development (as is the case of childhood) could provide acute cognitive benefits [152]. Therefore, a double-blind, counterbalanced, crossover intervention study showed that acute supplementation with haskap berry extract "*Lonicera caerulea* L." (200 and 400 mg anthocyanins) raised the episodic memory and exerts benefits in cognitive performance following a single acute dose in older adults compared to placebo [153].

These findings support that the consumption of berries produces beneficial effects on cognition in humans, which are probably related to the effects of the berries on the nervous system. For example, blueberry diets are associated with enhanced working memory which is accompanied by an increase in the neurogenesis of the hippocampus [17]. A randomized, controlled, double-blind, crossover studio showed that the administration of 766 mg total blueberry polyphenols in healthy young men reduced neutrophil NADPH oxidase activity at 1, 2, 4, and 6 h after consumption [154]. In this sense, NADPH oxidase has been shown to play an important role in oxidative stress induction in the brain [155], because it uses oxygen and NADPH to generate superoxide [156]. Therefore, the administration of blueberry could be generating a reduction of superoxide and indirectly preventing oxidative stress events a long term. The mechanisms by which flavonoids and polyphenols exert these actions on cognitive performance are still being studied, including evidence suggesting that they can increase brain blood flow, as well as modulate the activation state of neuronal receptors, signaling proteins, and gene expression [157].

### **6. Berry side or toxicity effect**

According to our knowledge, there are some reports relating berry consumption in humans with side effects or toxicity. Data of toxicity in vivo was reported in 1997, in a study of the relation between flavonoid intake and subsequent cancer risk in 9959 Finnish men and women, aged 15–99 years and who are initially cancer free. Food consumption and dietary history method calculated the consumption of lingonberries, blueberries, black currants, raspberries, and gooseberries. People with higher consumption of berries were found to have a high risk of lung cancer. Apparently, the phenolic compounds produce toxicity proliferating cancer cells, but are not toxic in healthy cells [49].

Another study of 5-weeks-old Swiss Webster male mice, supplemented with lyophilized nightshade berries (*Solanum dulcamara*, 8 g/kg) with two different stages of maturity, showed that immature fruit supplementation produced gastrointestinal lesions; however, this condition was not observed in mice administered with mature lyophilized fruit. The authors concluded that these effects were attributed to the presence of saponin in the immature fruit [158]. In 2015, the first toxicity report by *Solanum dulcamara* was reported in a dog puppy (Labrador Retriever); the toxicity was attributed to steroidal glycoalkaloid solanine. After causing vomiting to the dog, dried stems and immature berries were observed, and gastric contents were evaluated by a local botanist identifying *Solanum dulcamara* intake, concluding that dog poisoning was due to the consumption of this fruit [159].

Another report was in 2009, when dozens of dead cedar waxwings in Thomas County, Georgia, USA, were found. In this case report, after evaluating five birds, the investigation group observed pulmonary, mediastinal, and tracheal hemorrhages and also found berries (*Nandina domestica* Thunb.) intact and partly digested into the gastrointestinal tracts. Due to their voracious feeding behavior, these birds ingested toxic doses of *N. domestica* and at the same time high concentrations of cyanide present in fruit berry [160]. It is important to note that *S. dulcamara* and *N. domestica* species are found wildly and are not consumed by humans.

**41**

action.

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

Regarding berries supplementation and synergy, it is recently reported that gallic acid, quercetin, ellagic acid, and cyanidin have a market antioxidant activity [161, 162], due to the synergistic effects between the numbers of aromatic ring mixtures. In addition, polyphenols present in berries can interact between them, improve their antioxidant properties, and, therefore, increase human's health benefits [162]. According to our knowledge, no studies were found related with pharmacological interactions and berry supplementation. It is necessary to carry out studies involving pharmacological molecules, berries' activities, and their phenolic compounds in order to generate new therapies and identify the existence

According to the research reported in this chapter, the supplementation of berries and their bioactive compounds as flavonoids, polyphenols, and anthocyanin

The objective of this research is to contribute with knowledge to the development of new strategies for the treatment of diseases such as anxiety, depression, AD, and PD, which includes natural products, particularly berry fruits that work as

A further evaluation of fruits berry supplementation in neural processes is required, as well as the identification of the effect of each particular bioactive compound on psychiatric and neurological disorders. More studies will be necessary to identify the mechanisms of action of this substance. It is also important to understand the scope in other neural processes and their application, effectiveness, synergy, pharmacological interaction, and side or toxic effects at clinical and

The present chapter evidenced a number of investigations in vivo related with the use of different berry fruit supplement doses, not only in humans but also in animal models. These results suggest the potential health effect of berries due to bioactive compounds mainly flavonoids, polyphenols, and anthocyanins, used commonly for its antioxidant capacity. According to our knowledge, the cases reported in the literature by animal toxicity are related with the consumption of wild berries. In humans the relationship between phenol compound consumption and lung cancer has been reported; however, there is no evidence of side or toxic effects related with berry supplementation or their bioactive compounds, and pharmacological interaction related to their consumption due to no dietary intervention

In addition, berry consumption has shown to be effective in a number of cardiovascular and metabolic diseases, and also recent investigations are proposed for the management of berry fruit supplementation as neuroprotector and the reduction of symptoms in diseases such as anxiety, depression, AD, and PD, among others. The use of this biological berry compounds might promote an alternative for prevention and give excellent opportunities for human nutrition as a functional food and nutraceutical. Future research in this field is necessary, in order to clarify and support the evidence of the effects of flavonoids, polyphenols, and anthocyanins at the brain level, as well as their potential direct and indirect mechanisms of

suggests a potential health benefit for human nutrition.

preventive or coadjuvant therapy in the treatment of these diseases.

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

of side or toxic effects.

**7. Final comments**

preclinical levels of studies.

studies has been reported.

**8. Conclusions**

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

Regarding berries supplementation and synergy, it is recently reported that gallic acid, quercetin, ellagic acid, and cyanidin have a market antioxidant activity [161, 162], due to the synergistic effects between the numbers of aromatic ring mixtures. In addition, polyphenols present in berries can interact between them, improve their antioxidant properties, and, therefore, increase human's health benefits [162]. According to our knowledge, no studies were found related with pharmacological interactions and berry supplementation. It is necessary to carry out studies involving pharmacological molecules, berries' activities, and their phenolic compounds in order to generate new therapies and identify the existence of side or toxic effects.

## **7. Final comments**

*Behavioral Pharmacology - From Basic to Clinical Research*

**6. Berry side or toxicity effect**

are not toxic in healthy cells [49].

a single acute dose in older adults compared to placebo [153].

the wild blueberry drink during the critical period of development (as is the case of childhood) could provide acute cognitive benefits [152]. Therefore, a double-blind, counterbalanced, crossover intervention study showed that acute supplementation with haskap berry extract "*Lonicera caerulea* L." (200 and 400 mg anthocyanins) raised the episodic memory and exerts benefits in cognitive performance following

These findings support that the consumption of berries produces beneficial effects on cognition in humans, which are probably related to the effects of the berries on the nervous system. For example, blueberry diets are associated with enhanced working memory which is accompanied by an increase in the neurogenesis of the hippocampus [17]. A randomized, controlled, double-blind, crossover studio showed that the administration of 766 mg total blueberry polyphenols in healthy young men reduced neutrophil NADPH oxidase activity at 1, 2, 4, and 6 h after consumption [154]. In this sense, NADPH oxidase has been shown to play an important role in oxidative stress induction in the brain [155], because it uses oxygen and NADPH to generate superoxide [156]. Therefore, the administration of blueberry could be generating a reduction of superoxide and indirectly preventing oxidative stress events a long term. The mechanisms by which flavonoids and polyphenols exert these actions on cognitive performance are still being studied, including evidence suggesting that they can increase brain blood flow, as well as modulate the activation state of neuronal receptors, signaling proteins, and gene expression [157].

According to our knowledge, there are some reports relating berry consumption in humans with side effects or toxicity. Data of toxicity in vivo was reported in 1997, in a study of the relation between flavonoid intake and subsequent cancer risk in 9959 Finnish men and women, aged 15–99 years and who are initially cancer free. Food consumption and dietary history method calculated the consumption of lingonberries, blueberries, black currants, raspberries, and gooseberries. People with higher consumption of berries were found to have a high risk of lung cancer. Apparently, the phenolic compounds produce toxicity proliferating cancer cells, but

Another study of 5-weeks-old Swiss Webster male mice, supplemented with lyophilized nightshade berries (*Solanum dulcamara*, 8 g/kg) with two different stages of maturity, showed that immature fruit supplementation produced gastrointestinal lesions; however, this condition was not observed in mice administered with mature lyophilized fruit. The authors concluded that these effects were attributed to the presence of saponin in the immature fruit [158]. In 2015, the first toxicity report by *Solanum dulcamara* was reported in a dog puppy (Labrador Retriever); the toxicity was attributed to steroidal glycoalkaloid solanine. After causing vomiting to the dog, dried stems and immature berries were observed, and gastric contents were evaluated by a local botanist identifying *Solanum dulcamara* intake, concluding that

Another report was in 2009, when dozens of dead cedar waxwings in Thomas County, Georgia, USA, were found. In this case report, after evaluating five birds, the investigation group observed pulmonary, mediastinal, and tracheal hemorrhages and also found berries (*Nandina domestica* Thunb.) intact and partly digested into the gastrointestinal tracts. Due to their voracious feeding behavior, these birds ingested toxic doses of *N. domestica* and at the same time high concentrations of cyanide present in fruit berry [160]. It is important to note that *S. dulcamara* and *N. domestica* species are found wildly and are not consumed by humans.

dog poisoning was due to the consumption of this fruit [159].

**40**

According to the research reported in this chapter, the supplementation of berries and their bioactive compounds as flavonoids, polyphenols, and anthocyanin suggests a potential health benefit for human nutrition.

The objective of this research is to contribute with knowledge to the development of new strategies for the treatment of diseases such as anxiety, depression, AD, and PD, which includes natural products, particularly berry fruits that work as preventive or coadjuvant therapy in the treatment of these diseases.

A further evaluation of fruits berry supplementation in neural processes is required, as well as the identification of the effect of each particular bioactive compound on psychiatric and neurological disorders. More studies will be necessary to identify the mechanisms of action of this substance. It is also important to understand the scope in other neural processes and their application, effectiveness, synergy, pharmacological interaction, and side or toxic effects at clinical and preclinical levels of studies.

#### **8. Conclusions**

The present chapter evidenced a number of investigations in vivo related with the use of different berry fruit supplement doses, not only in humans but also in animal models. These results suggest the potential health effect of berries due to bioactive compounds mainly flavonoids, polyphenols, and anthocyanins, used commonly for its antioxidant capacity. According to our knowledge, the cases reported in the literature by animal toxicity are related with the consumption of wild berries. In humans the relationship between phenol compound consumption and lung cancer has been reported; however, there is no evidence of side or toxic effects related with berry supplementation or their bioactive compounds, and pharmacological interaction related to their consumption due to no dietary intervention studies has been reported.

In addition, berry consumption has shown to be effective in a number of cardiovascular and metabolic diseases, and also recent investigations are proposed for the management of berry fruit supplementation as neuroprotector and the reduction of symptoms in diseases such as anxiety, depression, AD, and PD, among others. The use of this biological berry compounds might promote an alternative for prevention and give excellent opportunities for human nutrition as a functional food and nutraceutical. Future research in this field is necessary, in order to clarify and support the evidence of the effects of flavonoids, polyphenols, and anthocyanins at the brain level, as well as their potential direct and indirect mechanisms of action.
