Neuroprotective Potential of Berry Fruits in Mitigating Neurodegenerative Diseases: A Focus on Huntington’s Disease

Abstract

A berry is a small edible fruit that is often pulpy. Berries can be juicy, round, colorful, pit-free, sweet, sour, or tart, and they can have a lot of pip or seed within. Blackberries, red berries, blueberries, bill berries, blackcurrant berries, and strawberries, among other berries. All across the world, berries are a popular ingredient in cakes, pies, jams, and preserves. Certain berries have substantial commercial value. The berry industry and the types of cultivated and wild berries differ from country to country. According to current clinical trials, berry fruits improve motor and cognitive capacities and help prevent age-related neurodegenerative diseases (NDD). Additionally, the berry fruits have the ability to modify signaling pathways linked to neurotransmission, neuroplasticity, inflammation, and cell viability. The neuroprotective properties of fruits and berries are associated with phytochemicals such as tannin, anthocyanin, quercetin, catechin, kaempferol, and caffeic acid. Blackberries, red berries, blueberries, bill berries, mulberries, blackcurrants, and blackberries Berries on neurodegenerative illnesses: Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, ischemia diseases; raspberries; goji berries; acai berries; Cranberries; Straw berries. Scientists claim that berries are among the healthiest foods to consume for vitamins, minerals, and compounds that fight disease. Additionally, berries may reduce the risk of some age-related neurological conditions in society. We tried to succinctly illustrate the benefits of several berries for neurological disorders and neurological diseases.

1. Introduction

The term neurodegenerative originates from the “prefix” “neuro-,” signifying nerve cells and neurons, and “degeneration,” indicating the process of losing organs or tissue function. Therefore, any degenerative condition that predominantly damages neurons in the strictest meaning of the word is referred to as neurodegeneration. As a class of neurological disorders, neurodegenerative diseases affect express groups of neurons in clear-cut functional anatomic systems and can manifest in a wide range of clinical and compulsive ways. They grow quickly and produce for unclear causes. Since they are not considered essential neuronal diseases, edema, neoplasms, bleeding, and nervous system trauma are not classified as neurodegenerative disorders. diseases known as neuropathologies, in which the death of neurons is caused by known factors such as hypoxia, poisoning, metabolic errors, or infections. which are not primary neural diseases, neurodegenerative disorders, or nervous system diseases that affect neurons rather than their basic makeup, such as the myelin sheath present in some forms of sclerosis. Similar to Alzheimer’s disease, Huntington’s disease, and Parkinson’s disease, the majority of attention has thus far been given exclusively to a small number of the numerous neurodegenerative disorders [1]. Global health is severely challenged by neurodegenerative diseases, among which Huntington’s disease is one of the most severe forms. A search for efficacious neuroprotective tactics has prompted scholars to investigate the possible advantages of natural substances, and the neuroprotective characteristics of berry fruits have garnered notice in the past several years. The purpose of this chapter is to examine how berry fruits can help to mitigate neurological diseases, including Huntington’s disease.

2. Huntington’s disease

The hallmarks of HD, an autosomal dominant neurodegenerative disease, are impaired motor coordination and cognitive impairment. The development of the CAG trinucleotide repeat, which codes for a poly-glutamine (poly Q) pattern in the Huntington (htt) protein, is responsible for Huntington’s disease [2]. The peri-nuclear cytoplasmic totals and intracellular considerations that poly-glutamine-htt structures can be broken down by the autophagy process [3]. Previous investigations have shown that in models of Huntington’s disease, pharmacological and genetic inhibition of macro-autophagy prevents the mutant from being free and eliminates the neurotic symptoms. However, in certain types of Huntington’s disease, the activation of macroautophagy facilitates the evacuation of both totaled and solvent HTT and lessens their destructiveness [4]. Similarly, in a mouse model of Huntington’s disease, artificial enhancement of chaperone-mediated autophagy concentrating of mutant htt with connector particles sufficiently reduces levels of this harmful protein and increases the disease aggregation suggesting that chaperone-mediated autophagy is a further mechanism of htt debasement. Although htt mutants and totals are substrates for autophagy, the htt protein itself may function as a regulator of autophagy. In cells and mice, overexpression of a full-length htt that fails to meet the poly-glutamine (poly Q) stretch stimulates autophagy activation and guarantees reduced destructiveness of the mutant poly-glutamine (poly Q)-htt. [5]. Autophagy’s participation in HD is further supported by the sequestration of mammalian target of rapamycin (mTOR), a main negative regulator of autophagy, in mutant httaggregates. This results in reduced mTOR activity and autophagy activation (Figure 1) [6].

Figure 1.

Auto-phagy in HD: is linked with defective cargo recognition, which contribute’s to htt [6].

3. Elderberries

Throughout medical history, medicinal plants have been employed to treat a wide range of diseases, including diabetes, the common flu, heart disease, and other conditions. Grown across North America, Europe, Asia, and North Africa are elderberries (Sambucus spp.). Elderberry (EB) has been shown in recent research to lessen the symptoms of various viral infections [7]. North African traditional medicine uses all parts of EB, but studies have revealed that the berries and flowers contain the highest concentration of flavonoids (such as quercetin and rutin) and anthocyanins (such as cyanidin 3-O-sambubioside and cyanidin 3-O-glucoside), which are antioxidative and anti-inflammatory agents and are most abundant in EB compared to other berry species polyphenols [8]. According to several recent studies [9, 10, 11], the EB fruit can inhibit lipopolysaccharides (LPS) or interferon gamma (IFNγ), which attenuates the inflammatory response and oxidative stress and suppresses the production of proinflammatory mediators like nitric oxide (NO) and ROS. According to some previous research, EB can lessen the loss of neuronal cells by reducing microglial activation, among other neuroprotective effects [12, 13]. Recently, there has been an increasing amount of research on the use of herbal remedies, such as rutin’s impact on neurodegenerative diseases including HD and Alzheimer’s disease, to treat and even lessen their symptoms [14]. According to Kreilaus et al. [15], an additional investigation has demonstrated that anthocyanins delay the onset of motor impairment in female HD rats. The purpose of this investigation was to determine whether EB could enhance neuronal survival in rats treated with 3-nitropropionic acid (3-NP), a neurotoxic, and mitigate its apoptotic, oxidative, and inflammatory effects.

4. Cranberry juice (CJ)

According to Kalai et al. [16], Parkinson’s disease (PD) is a neurodegenerative disorder marked by motor dysfunction caused on by the loss of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNpc) and the presence of Lewy bodies in the brain, which are primarily made up of aggregated α-synuclein (ASN). Cranberry juice (CJ) is thought to contribute to the many health advantages of this fruit since it is a rich source of polyphenols with potent antioxidant activity. However, there are currently very few in vitro research that have contributed to our understanding of cranberry’s neuroprotective potential. It has recently been discovered that CJ therapy reduces oxidative stress in a number of organs, with the brain showing the greatest benefit [17].

5. Goji berries

Possess a variety of bioactivities and are utilized as food or in traditional medicine. This study investigated the anti-inflammatory and antioxidant properties of methanolic extracts from red and black goji berries. Inflammation and the resulting oxidative stress have been connected to a number of chronic diseases, including neurological conditions. Based on our research, it appears that these goji berries, particularly the dark ones, may contain chemicals that might be used pharmacologically to treat inflammatory and oxidative disorders [18].

6. Açai berry

Here, we found that açai berries could reduce behavioral alterations caused by VaD in the CA1 and CA3 areas, as well as hippocampal mortality. Supplements that harness the preventative qualities of açai berries may be beneficial for the future management of vascular dementia [18].

7. Strawberry

The tree strawberry is native to the Mediterranean region and is also cultivated in Eastern Europe. The broad range of antioxidants in strawberries makes them a food that supports “health.” The most common antioxidants are flavonoids, caffeic acid, ellagic acid, anthocyanins, catechin, kaempferol, gallic acid, derivatives, vitamins C and E, and carotenoids [18]. The Morris water maze serves as an example of how strawberries might improve cognitive performance. A recent study found that strawberries can improve the motor behavior and rod-walking performance. These findings suggest that the phytochemicals included in strawberries can help with age-related deficiencies in addition to their well-established benefits on heart disease and cancer [18].

8. Bilberry

Bilberries provide a lot of health benefits because of their high levels of anthocyanin, flavonol, vitamin C, E, and manganese as well as carotenoid, lutein, and zeaxanthin content. The biological effects can protect blood vessels and improve blood circulation. These effects include benefits for the health of the mouth, gums, and eyes in addition to strong anti-inflammatory, antioxidant, and anti-hyperglycemic properties. There aren’t many appropriate animal models available to study the impact of extra antioxidants on age-related memory and learning deficits. OXYS rats, who have inherited features of accelerated ageing and high oxidative stress sensitivity, are among the possible genetic murine models. These rats have a severely shortened lifespan (28% fewer years than Wistar rats). Because of this, OXYS rats have been employed as an experimental model to elucidate the basic mechanisms behind age-related changes in brain functions, such as deficiencies in learning and cognition in diseases associated with aging. It is well known that the generation of reactive oxygen species (ROS) can activate the activation of many genes in cells that generate antioxidant-containing proteins. The information previously presented supports the theory that a decline in antioxidant protein production and activity within cells is one of the main causes of aging and neurological disorders. It was also shown that the bilberry extract increased the activity of the enzyme dismutase superoxide in the brain and reduced lipid peroxides. Furthermore, long-term bilberry extract shields OXYS animals from deficits in memory and learning. A fruit flavonoid found in bilberries may be combating illness. including fruits, berries (including mulberries, blackcurrant, blackberry, blueberry, and strawberry) can help prevent neurological and neurodevelopmental diseases. Examples of berries that can help include goji berries, elderberries, and raspberries. Berries: Blackberries, blueberries, raspberries, blackcurrants, and mulberries may possess neuroprotective qualities (Table 1) [18].

Table 1.

Structures of important active compounds of the berry fruits.

9. Blackcurrant

One fruit that may be able to help with AD neuroprotection is blackcurrant. Anthocyanins, a kind of polyphenols found in abundance in blackcurrant, make up approximately 80% of all components that have been measured [18]. Additionally useful in halting the production of ROS in the presence of -Amyloid (A) are the flavonols found in blackcurrant. Polyphenolic chemicals found in blackcurrant fruits have been demonstrated to possess antimicrobial, antioxidant, antiviral, and antibacterial properties. They also found that cells exposed to blackcurrant extracts high in anthocyanins generated much fewer reactive oxygen species (ROS). Polyphenols present in bilberries and blackcurrants have been shown to inhibit the formation and elongation of fibrils and to destabilize the generated An in vitro fibril. Blackcurrant and bilberry-supplemented diets also reduced the behavioral deficits in APdE9 mice [18]. In a demanding swimming setting, a black currant diet increased swimming speed, disproving the theory that this is the result of a motor deficit. The berry extracts were also found to have a somewhat favorable effect in the Morris swim test, where fed mice with bilberry and blackcurrant spent less time on the pool wall and made fewer search rotations when swimming [18].

10. Blackberry

Blackberry fruits are well recognized for their high tannin content, cyaniding-3-O-glucoside, salicylate, rich polyphenols, folate, manganese, fiber, vitamin C, and antioxidants. Blackberries possess biological properties such as antioxidant, antiseptic, antibacterial/antiviral, anti-hyperglycemic, and anticancer activities. In addition, they can lessen pain, prevent the aging process, restore normal cholesterol levels, and enhance blood flow. found that wild blackberries from Braganc (northern Portugal), including brigantinus and vagabundus, exhibited attainable neuroprotective benefits through altering glutathione levels, reducing intracellular ROS levels, and preventing the onset of caspases during treatments. These effects on neuronal cells reduced oxidative damage, one of the most important components of neurodegeneration. Studies conducted in vitro suggest that blackberries possess potent anti-inflammatory and antiproliferative properties. Furthermore, older rats taking part in motor neuron tests performed better behaviorally due to the antioxidants in these fruits. Additionally, improved measurements of balance, fine motor coordination, and spatial working memory and learning were found in the (MWM) testing [18].

11. Mulberry

Mulberries (Morus alba L., Moraceae) are used as a diuretic, anti-inflammatory, antitussive, antipyretic, and anti-hyperglycemic in oriental traditional medicine. In PC12 cells that had been starved of glucose and oxygen, C3G increased cell viability. Further studies have revealed that mulberry fruit extract guards against oxidative stress caused by ischemia in both in vitro and in vivo models, suggesting that C3G is an essential part of the fruit extract that does this. Berries, especially those like strawberries, bilberries, blackcurrants, blackberries, blueberries, and mulberries, can have neuroprotective qualities, just like fruits (Table 2). Through modifications to cell signaling that improve or support brain communication, calcium buffering, neuroprotective stress shock proteins, plasticity, antioxidant/anti-inflammatory action, stress signaling pathways, and acetylcholinesterase inhibition, the berry fruit may also have direct impacts. Through these changes and others that are being studied, berries may enhance cognitive and motor behavioral performance. Dietary treatments high in phytochemicals (e.g., anthocyanins and caffeic acid), such as berry fruits, may be effective in guarding against ageing by reducing or delaying the onset of age-related neurodegenerative disorders (Figure 2). Extensive clinical trials are necessary to confirm the effects of berry fruits and generate novel therapeutic medications for brain-related diseases [18].

Natural compounds	Class/mechanism/therapeutic mode	Therapeutic effect
Strawberry	Stimulated guanine triphosphatease activity inhibition Reducing oxidative stress Cyclooxegenase Anti-inflammatory activity	Improving Morris water maze performance Preventing neurochemical and behavioral changes Anti-inflammatory activity
Bilberry and blackcurrant	Decreasing the ratio of insoluble amyloid beta-42/40	Alleviating behavioral abnormalities
Bilberry	Free radical scavenging activity Alleviating memory deficits	Alleviating memory deficits
Blackberry	Reducing intracellular reactive oxygen species levels, modulating glutathione levels and inhibiting caspases activity	Improving behavioral performance in motor tests and Morris water maze (cognitive test)
Blueberry	Changes in brain-derived neurotrophic factor Decreasing Aβ levels Decreasing the levels of interleukin-1β, tumor necrosis factor-α and transcription factor nuclear factor-kappaB	Enhancing motor and memory performances Significant cognitive enhancement
Mulberry	Decreasing the infarct volume of the brain	Neuroprotection

Table 2.

Neuroprotective effects of berry fruits [18].

Figure 2.

Graph illustrating the potential defense mechanism of berries and fruits against (NDD) [18].

12. Blueberry

Blueberries are rich in flavonoids, including hydroxycinnamates, flavanols, anthocyanins, and caffeic acid. Consuming blueberries can improve vascular health, lower inflammation, prevent kidney damage, and lower oxidative stress. These benefits have been linked to their relatively high flavonoid content, especially in anthocyanins. A new study suggests that anti-aging and high-fat diet-related behavioural alterations may be addressed by supplementing with blueberries. An imbalance in calcium homeostasis and the accumulation of protein AB exacerbate oxidative damage, ageing, and neurodegeneration. inhibition of PKA by A alone or in conjunction with glutamate in embryonic neurons, as well as CREB, a downstream signaling target of PKA. Learning and memory are tightly associated with CREB at the synaptic sites affected by AD. Associated The problem is further complicated by age differences in memory, signal processing, and sensitivity to Reactive Oxygen Species. shown that, when administered in a designated culture media, blueberry extract therapy protects against A42 in aged middle (isolated neurons in 10–12 months) and elderly (neurons isolated approximately 24 months) neurons. A-42 toxicity was decreased in middle-aged and elderly hippocampal neurons after treatment with blueberry extract. When aged neurons get A treatment, their glutathione levels rise in tandem with the age-dependent enhancement of pERK signaling, which causes the largest increase in MAPK activity. Because blueberry extract reduces ROS production and transient stress signaling, it can improve cognitive function in aging rats. By using a ROS stress response, blueberry extract pretreatment prevents calcium dysregulation and blocks CREB and ERK activity. A preclinical study found that supplementing with blueberries enhanced motor and cognitive performance in an animal model of aging. Spatial memory alterations in the mice receiving blueberry supplements are effectively avoided by blocking the CREB/brain-derived neurotrophic factor pathway. Moreover, the distribution of anthocyanins in the hippocampus may be related to increased neuronal signaling there. These results support the hypothesis that flavonoids, particularly anthocyanins, may enhance cellular signaling and lessen oxidative damage. These results also suggest that flavonoids may directly affect cognition, which may help halt the degenerative processes of the brain brought on by aging and disease. There is evidence that supplementing with blueberries not only improved Morris water maze performance but also effectively reversed the cognitive impairments in object recognition. When animals were given blueberries, there was a significant decrease in Caspase-3 activity in the ischemic hemisphere. Regular consumption of blueberries reduces the effects of ischemia/reperfusion-induced brain infarction and apoptosis. Furthermore, there were more striatal TH-positive nerve fibers in mice given a diet enriched with blueberries. Adult mice (3-month-old mice) that received blueberry supplements showed less DNA damage in the hippocampus and cerebral cortex and performed better on memory tests. Including blueberries in your diet can help you feel better since they increase your antioxidant levels, fight inflammation, regulate different signaling pathways at different times, and fix anomalies in your cognitive function. A brief blueberry-enriched diet both prevents and reverses deficits in object recognition memory in elderly Fischer-344 rats. demonstrated that administering a 12-week dose of wild blueberry juice to elderly individuals experiencing mild memory decline improved their memory. The central cholinergic system is responsible for controlling cognitive functions. Treatment of cognitive deficits with acetylcholinesterase inhibitors and cholinergic receptor antagonists has resulted in increased levels of endogenous acetylcholine. The enzyme acetylcholinesterase transforms acetylcholine into choline and acetyl-coenzyme (2009). Giving a polyphenol-rich wild blueberry extract to healthy adult mice decreased acetylcholinesterase activity, increased ascorbate and glutathione levels, and relieved brain oxidative stress (MDA levels), according to research by A. Papandreou et al. Therefore, by increasing antioxidant levels in the brain and lowering acetylcholinesterase activity, feeding adult mice with blueberry extract containing concentrated polyphenols enhances their cognitive function. These results highlight the significant impact of the bioactive components of wild blueberries on brain function. demonstrated that the polyphenols in blueberries prevented rats’ kainic acid-induced learning deficits, which were similar to those observed in elderly animals. Blueberry polyphenols alter the expression of genes linked to inflammation, so mitigating the detrimental impact of an inflammatory stimulation on the brain. The histological and clinical features of experimental autoimmune encephalomyelitis, including as inflammation and neurodegeneration, are similar to those of multiple sclerosis. As per a report conducted by [18].

13. Raspberry

The immature fruit known as palm leaf raspberry (Rubus chingii Hu) is a member of the Rosaceae family and the Rubus genus. It is a significant Chinese herbal remedy that has both therapeutic and nutritional value as food [19]. Additionally, the Chinese Pharmacopeia had it. In traditional Chinese herbal medicine, raspberries are frequently used as a tonic to treat a variety of ailments, including enuresis, impotence, kidney shortage, and frequent urination. It has a wide range of pharmacological actions, including anti-inflammatory, anti-cancer, and memory-enhancing. Recent studies on the pharmacological actions of raspberry have revealed that it also possesses memory-improving, anti-aging, anti-anxiety, and anti-AD qualities [20]. Numerous research have demonstrated the beneficial effects of raspberry polyphenols on oxidative stress, inflammatory responses, and cardiovascular disease [21, 22]. However, there hasn’t been much research done on raspberry polyphenols’ potential to treat Alzheimer’s disease.

14. Berry fruits and neuroprotection

Strawberries, blackberries, blueberries, and raspberries are a few examples of berries that are high in bioactive substances like flavonoids, polyphenols, and antioxidants. It has been demonstrated that these substances have neuroprotective, anti-oxidative, and anti-inflammatory qualities. According to a number of studies, eating berry fruits on a daily basis may improve cognitive function and maybe lower the risk of neurodegenerative diseases.

15. Mitigating Huntington’s disease

A genetic neurodegenerative condition known as Huntington’s disease is marked by gradual motor impairment, cognitive decline, and psychiatric symptoms. A huntingtin gene mutation that results in the synthesis of a harmful mutant protein is the fundamental cause of the disease. The possibility of berry fruits to lessen the consequences of Huntington’s disease has been investigated recently.

16. Anti-inflammatory effects

Due to their anti-inflammatory properties, berry fruits may help reduce the neuroinflammation linked to Huntington’s disease. Neurodegenerative diseases are characterized by chronic inflammation, and berry chemicals’ anti-inflammatory qualities may be able to reduce the brain’s inflammatory response.

17. Antioxidant properties

Another factor that contributes to the development of Huntington’s disease is oxidative stress. By scavenging free radicals, the antioxidants in berry fruits may prevent oxidative damage and shield neurons from deterioration. This antioxidant defense system could aid in reducing the course of the disease.

18. Neurogenesis and cognitive enhancement

According to certain research, eating berries could promote neurogenesis—the process of creating new neurons. Given that one of the main symptoms of Huntington’s disease is neuronal loss, this may be especially helpful. Furthermore, in patients with Huntington’s disease, increases in cognitive performance linked to berry eating may improve general brain health.

19. Literature review

Khan et al. [18] Suggested vitamin C may have an anticancer mechanism in addition to its anti-inflammatory and strong antioxidant properties, making it useful in the treatment of neurological disorders, liver problems, renal disease, and heart disease. Additionally, it will examine how vitamin C, a protective factor, mitigates Pb-induced toxicity in both people and animals.

Khan et al. [18] reported that 6-Amino Flavone is a neuroprotective drug against Neurodegenerative disease and Neurological disorder.

Ahmad et al. [23] studied Because AD and depression are disorders associated with neuro-inflammation and neurotransmitter deficit, the effects of the aforementioned drugs and their active constituents improved neurodegenerative diseases, suggesting their therapeutic promise in these conditions.

Khan et al. [18] one of the information collected the naturally occurring chemical known as flavonoids is widely distributed across the kingdom of plants and is responsible for the various colors that plants show in their leaves, flowers, fruits, and seeds. These are plant secondary metabolites with potent antioxidant properties. Flavonoids have a variety of health benefits, including sedative, antioxidant, anticonvulsant, antidepressant, anti-inflammatory, anti-cancer, anti-microbial, antihypertensive, vasorelaxant, cardiac protective, antidiuretic, antiulcerogenic, antifungal, antiviral, antineoplastic, neuroprotective, and hepatoprotective qualities.

Khan et al. [24] concluded that 6-AF significantly improved behavior as measured by the Morris Water Maze (MWM) and the Y-maze. This improvement was followed by an inhibition of p-JNK and its downstream signaling, which included the proteins found in the mouse brain homogenates that were detected by western blotting, as well as TNF-alpha and Poly (ADP-ribosepolymerase-1 (PARP-1) (NF-KB). Furthermore, 6-AF also downregulated NRF-2 proteins in adult mice that were exposed to oxidative stress caused by Cd. Finally, 6-AF is an effective neuroprotective drug for neurological diseases.

20. Conclusion

Given how crippling Huntington’s disease is, it is critical to investigate neuroprotective tactics for reducing its effects. Berry fruits offer a prospective channel for intervention due to their high quantity of bioactive chemicals. Although more research is required to clarify the precise methods and dosage, adding berry fruits to the diet may provide a convenient and all-natural way to help those with Huntington’s disease. Further research into these substances could lead to the creation of complementary methods that lessen the impact of neurological diseases. Oxidative stress and inflammation are the primary drivers of ageing and the onset of age-related neurodegenerative diseases. Plant food matrices contain a variety of naturally occurring anti-inflammatory and antioxidant compounds, some of which can have neuroprotective effects. These compounds are primarily found in berries, which include strawberries, bilberries, blackberries, blueberries, and mulberries, as well as Goji berries, Elderberries, Cranberries, and Raspberry. The berry fruit may also impact cells directly by modifying cell signaling in a positive manner. Through these changes and others that are being studied, berries may enhance cognitive and motor behavioral performance. Berries and other dietary treatments containing phytochemicals (such caffeic acid and anthocyanins) may be an effective anti-aging medication because they can postpone or reduce the onset of age-related diseases (NDD). Comprehensive clinical trials need to be carried out in order to further validate the benefits of berry fruits and provide novel therapeutic medications for brain-related diseases.

Conflict of interest

The author declared there is no conflict of interest.