**4. Effect of polyphenol compounds in neurodegeneration**

## **4.1 Natural polyphenol products**

Polyphenols are natural compounds, generally secondary metabolites, produced by plants and found mainly in fruits, vegetables, and cereals and in their derivatives. Some of them are synthetized during the normal development of the plant while others are produced in response to stress stimuli [93, 94]. They exert their function acting during the phase of development, reproduction, nutrition, growth, and communication with other plants, as well as in plant defense mechanisms like resistance to microbial pathogens, herbivore, insects, and protection to UV-light radiation [95]. More than 8.000 polyphenols have been identified in different plant species. They all derive from common precursors like phenylalanine and shikimic acid [96]. Often, they are linked with a sugar through the hydroxyl moiety, directly to the aromatic ring or conjugated with other compounds [97]. Polyphenols are characterized by a minimal hydroxyphenyl structure, and despite the multitude of existing polyphenols, they are grouped into different classes according to the number of phenol rings. The main groups are phenolic acids, flavonoids, stilbenes, and lignans [98] (**Figure 6**).

#### **4.2 Potential therapeutic applications of polyphenols**

Several epidemiological studies have been reported concerning the potentiality of polyphenols compounds in disease treatment and prevention [99, 100]. Polyphenols exert a positive role in cardiovascular disease [101–103], diabetes [104, 105], cancer [106, 107], aging, and neurodegeneration [108, 109]. One of the main activities of polyphenol resides is their antioxidant properties. Indeed, they are capable to protect cells and macromolecules from oxidative damage which in turn leads to degenerative age-associated diseases [110, 111]. Nevertheless, polyphenol function is also bound to its action on enzymes, immune defense, inflammation, cell signaling, and other pathways critical for the onset of the disease [112]. All these properties make the polyphenols potential drugs for preventing and treating neurodegenerative diseases, in particular

**47**

*Polyphenols as Potential Therapeutic Drugs in Neurodegeneration*

AD and PD. Actually, these compounds have shown to be effective in epidemiological,

*Scheme of the main polyphenols and their chemical structures. Polyphenols are grouped into four principal classes: stilbenes, lignans, phenolic acids, and flavonoids. The last one is organized into six subclasses:* 

The effects of polyphenols on AD and PD can be divided into two main categories: the effects on nonamyloidogenic pathways (i.e., anti-oxidation pathway, interaction with cell signaling events, and interactions with enzymes) and the effects on amyloidogenic pathways. Below, the main beneficial effects shown by polyphenols

1.*Effects on memory*. One of the hallmarks of AD is the memory impairment. This can be due to deficiency of factors, such as the brain-derived neurotrophic factor (BDNF) and the accumulation of formaldehyde. Polyphenols have been shown to improve the long-term memory by increasing BDNF concentration *in* 

2.*Effects on inflammation pathway*. Inflammation plays an important role in the development of neurodegeneration. It is demonstrated that there is a correlation between the microglia activation and the neuroinflammatory response [116, 117]. Upon microglia activation, the transcription factor NF-kB (nuclear factor k-light-chain-enhancer of activated B cells) moves from cytoplasm to nucleus, inducing the expression of interleukins (i.e., IL-1β, IL-6, IL-12, and IL-23), other factors (i.e., TNF-α and iNOS), and cyclooxygenase 2 (COX-2). In this scenario, polyphenols can interact with certain types of kinases (including the mitogen-activated protein (MAP) kinase) preventing the activation of

*vivo* and decreasing the accumulation of formaldehyde [113–115].

*in vitro*, and pre-clinical studies, but not in the early phase of the disease.

**4.3 Polyphenols in Alzheimer's and Parkinson's disease**

*anthocyanins, flavonols, flavanols, flavanones, chalcones, and others.*

on AD and PD are analyzed.

**Figure 6.**

*DOI: http://dx.doi.org/10.5772/intechopen.89575*

*Polyphenols as Potential Therapeutic Drugs in Neurodegeneration DOI: http://dx.doi.org/10.5772/intechopen.89575*

#### **Figure 6.**

*Neuroprotection - New Approaches and Prospects*

negative implications, due to the alteration of its physiological equilibrium. Additionally, the transcription of the gene can be reduced. Clenbuterol was shown to be efficient in reducing Syn expression by 35% in neuroblastoma cell lines [88]. Some AD therapies based on the modulation of AD gene expression are proposed on the basis of the important progresses made in the understanding of the transcriptional regulation of some enzymes such as beta-secretase 1 (BACE1), apolipoprotein E (apoE), APP amyloid precursor protein (APP), and presenilin (PSEN) promoters [89]. Alternatively, to reduce the level of the active protein *in vivo*, its clearance can be enhanced. This can be obtained by increasing the intracellular degradation *via* autophagy or *via* the ubiquitin

2.*Protein aggregation inhibitors*. An attractive approach would be the use of small molecules able to bind the monomeric form of the protein preventing its assembly into potentially toxic aggregates. Unfortunately, it remains still unclear which conformation of these proteins must be targeted, since all of them are natively unfolded, and multiple and concurrent events contribute to their conversion in oligomers and fibrils [91]. In this ambit, the use of polyphenols is quite promising, and, as described below, these compounds exhibit in some

cases the ability to disaggregate preformed oligomers and fibrils [92].

Polyphenols are natural compounds, generally secondary metabolites, produced by plants and found mainly in fruits, vegetables, and cereals and in their derivatives. Some of them are synthetized during the normal development of the plant while others are produced in response to stress stimuli [93, 94]. They exert their function acting during the phase of development, reproduction, nutrition, growth, and communication with other plants, as well as in plant defense mechanisms like resistance to microbial pathogens, herbivore, insects, and protection to UV-light radiation [95]. More than 8.000 polyphenols have been identified in different plant species. They all derive from common precursors like phenylalanine and shikimic acid [96]. Often, they are linked with a sugar through the hydroxyl moiety, directly to the aromatic ring or conjugated with other compounds [97]. Polyphenols are characterized by a minimal hydroxyphenyl structure, and despite the multitude of existing polyphenols, they are grouped into different classes according to the number of phenol rings. The main groups are phenolic acids, flavonoids, stilbenes, and lignans [98] (**Figure 6**).

Several epidemiological studies have been reported concerning the potentiality of polyphenols compounds in disease treatment and prevention [99, 100]. Polyphenols exert a positive role in cardiovascular disease [101–103], diabetes [104, 105], cancer [106, 107], aging, and neurodegeneration [108, 109]. One of the main activities of polyphenol resides is their antioxidant properties. Indeed, they are capable to protect cells and macromolecules from oxidative damage which in turn leads to degenerative age-associated diseases [110, 111]. Nevertheless, polyphenol function is also bound to its action on enzymes, immune defense, inflammation, cell signaling, and other pathways critical for the onset of the disease [112]. All these properties make the polyphenols potential drugs for preventing and treating neurodegenerative diseases, in particular

**4. Effect of polyphenol compounds in neurodegeneration**

**4.2 Potential therapeutic applications of polyphenols**

**4.1 Natural polyphenol products**

system. This topic is excellently reviewed by Boland et al. [90].

**46**

*Scheme of the main polyphenols and their chemical structures. Polyphenols are grouped into four principal classes: stilbenes, lignans, phenolic acids, and flavonoids. The last one is organized into six subclasses: anthocyanins, flavonols, flavanols, flavanones, chalcones, and others.*

AD and PD. Actually, these compounds have shown to be effective in epidemiological, *in vitro*, and pre-clinical studies, but not in the early phase of the disease.

### **4.3 Polyphenols in Alzheimer's and Parkinson's disease**

The effects of polyphenols on AD and PD can be divided into two main categories: the effects on nonamyloidogenic pathways (i.e., anti-oxidation pathway, interaction with cell signaling events, and interactions with enzymes) and the effects on amyloidogenic pathways. Below, the main beneficial effects shown by polyphenols on AD and PD are analyzed.


proinflammatory mediators [118, 119]. Polyphenol compounds are able to protect cells from inflammation by acting on reactive oxygen species (ROS), decreasing the secretion of prostaglandin E2 [120–123] and increasing the amount of the regulatory enzyme sirtuin1 over sirtuin2, unbalanced after accumulation of Aβ [20]. Cell and PD-mouse model studies demonstrated that these compounds decrease the expression of NF-kB and other inflammatory factors [124–126].


**49**

*Polyphenols as Potential Therapeutic Drugs in Neurodegeneration*

**5. Polyphenols as a drug in the brain delivery system**

necessary to understand in detail BBB pathological aberrations.

Due to their safeness and tolerance [175–177], polyphenols are currently studied as neuroprotectors. It is important to point out that for exerting their action, polyphenols must accumulate in the brain in an active form and in sufficient concentration. The limiting step is choosing the right administration route. In most of the clinical studies, the oral administration is the preferred way, but recently the nasal delivery is taken into consideration for the easiness to bypass the BBB [178], the increased bioavailability, the decreased metabolism, and peripheral side effects [179, 180]. The major problem of oral administration relies on poor absorbance of the modified form of polyphenols (i.e., glycosides and ester polymers) in the upper portion of the gut leading to the passage in the colon in which polyphenols are converted by gut-microbiota in the aglycone form or other substances able to be better absorbed [181, 182]. Once absorbed, they can be further modified by enzymes and eliminated [183, 184] or adsorbed to plasmatic proteins (i.e., albumin) and then accumulated in different districts [185].

**5.1 Blood-brain barrier and neurodegeneration**

Their main activity regards the interaction with Syn monomers leading to protein stabilization and fibrillation prevention [92]. Another factor concerns the formation of not toxic off-pathway oligomers that do not form fibrils nor interact with the membrane [156, 157]. Some polyphenols are also able to interact with oligomeric and fibrillar species, leading to their destabilization [65, 92]. The major effect of polyphenols is due to the noncovalent interaction with the Syn C-terminal domain. In addition, these compounds can chemically modify the lysine residues, present mainly in the N-terminal region, through Michael addition and Schiff-base formation [158]. This reduces the conformational plasticity of Syn and its tendency to be converted into fibrils. Moreover, structureactivity relationship studies indicate that the differences in polyphenols activities reside in the number and position of OH groups in the phenyl ring [159].

The human brain comprises more than 600 km of blood vessels that guarantee oxygen, energy metabolites, and nutrients to brain cells and remove carbon dioxide and toxic metabolic products from the brain to the systemic circulation. A highly selective semipermeable border, called blood-brain barrier (BBB), separates the circulating blood from the central nervous system (CNS), regulating CNS homeostasis. Brain microvascular endothelia cells, neurons, astrocyte, pericytes, tight junctions, and basal membrane constitute tight brain capillaries in the BBB [160, 161]. It follows that BBB does not have fenestrations or other physical fissures for diffusion of small molecules. In fact, ions, solutes, and hormones can pass the BBB by passive diffusion through the paracellular pathway between adjacent cells. Hydrophilic biomolecules (i.e., proteins and peptides) can cross the BBB within specific and saturable receptor-mediated transport mechanisms [162]. The components of BBB constantly adapt in response to various physiological and pathological modifications into the brain [163, 164]. Loss of BBB integrity is correlated with vascular permeability increase, cerebral blood flow impairs, and hemodynamic response alteration [165]. In neurodegenerative disorders, endothelia degeneration leads to loss of tight junctions [166, 167], brain capillary leakages [168, 169], pericyte degeneration [170], endothelial cell remodeling [164], cellular infiltration [171, 172], and aberrant angiogenesis [173, 174]. All these BBB disruptions let different blood proteins (i.e., fibrinogen, plasminogen, and thrombin), water, and electrolytes to accumulate in different zones of CNS, enhancing the on progress of PD and AD [165]. Consequently, to project effective drugs for neurodegeneration, it is

*DOI: http://dx.doi.org/10.5772/intechopen.89575*

*Neuroprotection - New Approaches and Prospects*

proinflammatory mediators [118, 119]. Polyphenol compounds are able to protect cells from inflammation by acting on reactive oxygen species (ROS), decreasing the secretion of prostaglandin E2 [120–123] and increasing the amount of the regulatory enzyme sirtuin1 over sirtuin2, unbalanced after accumulation of Aβ [20]. Cell and PD-mouse model studies demonstrated that these compounds decrease the expression of NF-kB and other inflammatory factors [124–126].

3.*Effects on oxidative pathway, cell death and mitochondrial dysfunction*. In neurodegeneration, there is an uncontrolled production of free radicals and ROS that are not detoxified by the dedicated systems [127]. This leads to macromolecule damage and progressively to cell death [128]. Polyphenols lower the amount of ROS, increase the expression of enzymes, like glutathione, dedicated to scavenger the free radicals and prevent the disruption of mitochondrial membranes [129]. In addition, these compounds seem to prevent the lipid peroxidation [130]. These effects indirectly influence the fibrillation process of Syn, affected by some byproducts of lipid oxidation and peroxidation [131], as demonstrated in PD-animal model studies [132]. Moreover, polyphenols inhibit the cell death by acting on proteins involved in the apoptosis mechanism like Bcl/Bax, caspase 3, and protein kinases and by decreasing the accumulation of Aβ fibrils that exert cytotoxic effects [133, 134]. Another important scenario affected by polyphenols is the mitochondrial dysfunction (MD) that becomes increasingly important in the onset of PD [135]. Different factors play a pivotal role in MD: the presence of neurotoxin, Complex 1 deficiency (involved in mitochondrial electron transport), and penetration of mitochondrial membrane by amyloid aggregates [136, 137]. Polyphenol compounds exert their activity restoring membrane potential, increasing the expression and activity of the Complex 1 and scavenging the ROS, free radicals, and metals [138–141].

4.*Effects on acetylcholinesterase activity*. Nearly 30 years ago, dysfunction in the cholinergic system was found correlated with AD and cognitive impairment [142]. This dysfunction can be originated by a reduction in acetylcholine synthesis, reduced levels of choline acetyltransferase, reduced choline uptake, or cholinergic neurons degeneration [143]. The use of acetylcholinesterase inhibitors to restore the cholinergic pathway has proved to alleviate the cognitive dysfunction in neurodegenerative diseases [144]. Polyphenol compounds have shown to inhibit acetylcholinesterase, improving memory, learning, and cognitive functions [145].

5.*Effects on Aβ formation*. Polyphenol compounds act on the enzyme responsible for Aβ formation, decreasing the cleavage of APP into the peptide. They interact with and inhibit β-secretase [146]. In addition, they are able to restore the normal levels of γ-secretase, another enzyme involved in APP processing [147].

6.*Effects on the amyloidogenic pathways*. Polyphenols can act on Aβ monomer preventing its fibrillation, through the stabilization of the monomer and/or to the formation of an off-pathway oligomer. This can be due to the interaction of polyphenols with metal ions that promote the Aβ aggregation or to the noncovalent interaction with the peptide [148]. They are also able to disaggregate oligomers and fibrils, interacting with the β-sheet structure. This has been confirmed by *in vivo* studies where polyphenol intake reduces the amyloid deposit in the mouse brain [149, 150]. Polyphenols exert their anti-amyloidogenic action by interfering also with the aggregation of Tau [151–153], inhibiting Tau phosphorylation *in vitro* [154] and *in vivo* [155]. Several polyphenols have been tested for their anti-fibrillogenic properties *in vitro* and in PD-animal models.

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Their main activity regards the interaction with Syn monomers leading to protein stabilization and fibrillation prevention [92]. Another factor concerns the formation of not toxic off-pathway oligomers that do not form fibrils nor interact with the membrane [156, 157]. Some polyphenols are also able to interact with oligomeric and fibrillar species, leading to their destabilization [65, 92]. The major effect of polyphenols is due to the noncovalent interaction with the Syn C-terminal domain. In addition, these compounds can chemically modify the lysine residues, present mainly in the N-terminal region, through Michael addition and Schiff-base formation [158]. This reduces the conformational plasticity of Syn and its tendency to be converted into fibrils. Moreover, structureactivity relationship studies indicate that the differences in polyphenols activities reside in the number and position of OH groups in the phenyl ring [159].
