Bioactive Compounds Contained in Mediterranean Diet and Their Effects on Neurodegenerative Diseases Bioactive Compounds Contained in Mediterranean Diet and Their Effects on Neurodegenerative Diseases

Neuroinflammatory processes in the brain are believed to play a crucial role in the develop - ment of neurodegenerative diseases, especially due to increased production of reactive oxy gen species. The brain is susceptible to oxidative stress more than other organs due to the low activity of antioxidant defense systems. In agreement with these observations, increased oxi dative stress plays an important role in the pathogenesis of neurodegenerative diseases such as Alzheimer disease, Parkinson disease, ischemic diseases and aging. The Mediterranean diet is inspired by the traditional dietary pattern of some countries of the Mediterranean basin. From ancient times, these populations were characterized by simple food habits as high intake of whole cereals (pasta, bread, rice), fruits and vegetables (up to 400 g day −1 in Greece), legumes and fish, olive oil as the common source of fats, poor intake of meat and dairy products and a moderate, regular wine drinking. In the present chapter, there are going to be presented some bioactive substances present in the Mediterranean diet related to the prevention of neurodegenerative diseases. These substances are able to exert important antioxidant activity (through mechanisms such as sequestration of free radicals, inhibition of the production of hydrogen peroxide, activation of endogenous defense mechanisms.


Introduction
Neurodegeneration in Parkinson's, Alzheimer disease, and other neurodegenerative diseases seems to be multifactorial, in that a complex set of toxic reactions leads to the demise of neurons. Complications include: inflammation, glutamatergic neurotoxicity, increases in iron incidence of certain pathologies related to oxidative stress, chronic inflammation and immune system diseases such as cancer, atherosclerosis, cardiovascular disease and neurodegenerative diseases [13]. These reductions can be partially attributed to different bioactive compounds present in the Mediterranean diet (omega 3 fatty acids, polyphenols, resveratrol or melatonin). In fact, the five most important adaptations induced by the Mediterranean dietary pattern are [7] There is negative correlation between cognitive functions, saturated fatty acids and protective effect against cognitive decline with increased fish consumption, high intake of monounsaturated fatty acids and polyunsaturated fatty acids (PUFA), particularly n-3 PUFA [14]. Similarly, polyunsaturated and omega-3 fatty acids as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) supplements are associated with increased cognitive function, due to the cumulating of factors that ultimately favor membrane permeability and neuronal functioning [15].
There are numerous epidemiological studies relating the Mediterranean diet with the prevention of neurodegenerative diseases and minor cognitive decline [14,16]. However, other studies did not observe such relationship. Anastasiou et al. suggest that adherence to the Mediterranean diet is associated with better cognitive performance and reduced dementia in Greek elderly population [17]. Hardman et al. demonstrate that the relationship between Mediterranean diet score and cognition was only significant when medication use was taken into account.
In the present chapter, there are going to be presented some bioactive substances present in the Mediterranean diet related to the prevention of neurodegenerative diseases. These substances are able to exert important antioxidant activity (through mechanisms such as sequestration of free radicals, inhibition of the production of hydrogen peroxide, activation of endogenous defense mechanisms (catalase, superoxide dismutase), chelation of metals, etc.). However, many other biologically plausible mechanisms may be responsible for their protective effect [18,19] as follows: • Modulation of gene expression.
• Induction of cell death.
• Protection of DNA.
• Modification of cellular communication.
• Modification of the hormonal profile.
• Modulation of the lipid profile.
• Stimulation of the immune system. • Anti-inflammatory effect.

Resveratrol
Resveratrol belongs to the family of stilbenes and is one of the most studied polyphenols, mostly present in grapes and wines. This stilbene was discovered in 1940 in Veratrum grandiflorum by Takaoka [20] and reported in high concentration in Vitis vinifera in 1976 by Langcake and Pryce [21], leading to the subsequent research about bioactive function of the molecule (Figure 1). The scientific literature has reported several benefits related to resveratrol, most of them regarding to antioxidant capacity and cardiovascular improvement. However, pharmacokinetics of the molecule and the great content on red wine and grapes reveal resveratrol as an essential compound on the Mediterranean diet regarding neuroprotection.
Despite several studies regarding pharmacokinetics of resveratrol, it is still uncertain. Many scientific researchers have reported excellent values regarding in vitro bioavailability of resveratrol [22]. However, these values are not in agreement with in vivo results, mainly due to chemical insubstantiality [23]. In fact, revisions about pharmacokinetics differ widely between them about bioavailability of resveratrol. Fernández-Mar et al. reviewed knowledge on scientific literature, reporting a bioavailability of resveratrol over 70% [24]. Meanwhile, Ahmed et al. found a bioavailability minor than 1% after extensive revision of literature, reflecting the high discrepancies about the absorption of resveratrol [23].
Dietary sources of resveratrol comprise a wide variety of plant matrices [23]. Health benefits attributed to resveratrol were noticed by the scientific community, leading to the increment of scientific reports relating its presence in a wide range of plants. From now, resveratrol has been reported to be present in at least 72 plant derived foods [23,25]. As reported by Fernández-Mar et al. main sources of resveratrol comprise peanuts, pistachios, different berries, dark cocoa, and grapes/wine. All of them could be included in the Mediterranean diet; however, the main source of resveratrol in the Mediterranean diet are grape and derivatives, especially red wine [26][27][28][29]. Thus, concentration of trans-resveratrol in red wine can reach 14.3 mg/L, depending on the type of grape, cultivar conditions, or vinification procedures [23,[26][27][28][29].
Resveratrol is exclusively present in seeds and skin of grapes. Therefore, concentration of resveratrol in red wine is higher than white ones, due to the vinification process which leads to more extensive contact between skin/seeds and must [24]. As commented above, not only resveratrol has been found in grapes and must.
Other food with high amount of resveratrol are peanuts, in which resveratrol can be found in all edible parts of the plant. For example, peanut butter and peanut oil were found to have high quantity of trans-resveratrol reaching 16.9 μg/g in case of peanut oil [36,37].
Resveratrol has shown different pathways that could postpone neurodegenerative diseases onset, especially Alzheimer disease [23]. In 2017, Ahmed et al. published a revision about the role of resveratrol in Alzheimer disease and other neurodegenerative diseases. They showed a total of 18 recent publications about the different action of resveratrol in human organism [23].
As a summary, resveratrol leads to: • Inhibition of tauopathy.
• Enhancement of long-term memory formation.
• Inhibition of brain pro-inflammatory responses.
• Protection from oxidative injury.
• Inhibition of neurotoxicity by H 2 O 2 .
• Inhibition of synthesis of Aβ plaque.
• Prevention of neuronal death.
Cognitive impairment is also susceptible to be treated with resveratrol, as observed in animal models. Consequently, resveratrol might also be considered as a potential anti-depressant bioactive compound [28].
Neuronal deficiency originates from multiple neurodegenerative diseases. Resveratrol seems to be quite associated to the development of specific neurodegenerative diseases as Alzheimer disease or Huntington disease and Parkinson disease [29]. The most outstanding capacity of resveratrol that influences its effectiveness for the treatment of neurodegenerative diseases is the ability to penetrate the blood-brain barrier. In fact, it has demonstrated a great neuroprotective capacity, even in administration at low doses.
The activation of sirtuin-1 pathway (SIRT1) seems to be a determinant property of resveratrol [40,41]. Parker et al. [42] showed that by daily intake of one wine glass, it brings enough resveratrol (500 nM) to combat neuronal dysfunction caused in Huntington and Alzheimer's diseases through SIRT1 activation.
Regarding Parkinson's disease, the first advances regarding its relation with resveratrol were published in the year 2000 [43]. In mice, Karuppagounder et al. reported that daily intake of resveratrol decreased Aβ plaque in the CNS. Mayor changes were observed in the medial cortex, the striatum and the hypothalamus. Moreover, the most noticeable changes were observed deprived of the sirtuin-1 pathway, which enhances the hypothesis of reduced formation of Aβ plaque due to reduction cysteine and glutathione in the CNS [44].
One of the most studied characteristics of resveratrol is its ability to reduce oxidative injury. Reactive oxygen species (ROS) are mayor agents promoted unpaired oxidative stress, and are determinant for the production of oxidative injury and non-enzymatic lipid peroxidation. Oxidized lipoproteins stimulates apoptosis due to the union of DNA to NF-κB. Resveratrol acts inhibiting the activation of NF-κB, which reduces the possibility of oxidative injury at the Central Nervous System (CNS) [45,46].

Melatonin
Melatonin (N-acetyl-5-methoxytyramine) is a characteristic neurohormone of the pineal gland, also produced as a secondary metabolite in plants (Figure 2). It has been shown that synthesis of melatonin is produced from tryptophan, serotonin and N-acetylserotonin ultimately. On the other hand, melatonin molecule can also be formed by O-methylation of serotonin followed by N-acetylation of 5-methoxytryptamine in yeast [47,48].
The absorption of melatonin after oral intake has been previously approached by the scientific literature, reporting similar values between different researchers. Bioavailability reported values vary from 33 to 8.7% [49][50][51]. The absorption of melatonin is delimited by many parameters such as age, sex, season or circadian cycle. Nevertheless, there is variables such as elimination and distribution half-life that look to remains equivalent between subjects.
Nowadays, the claim accepted by the European Food Safety Authority concerning melatonin is related to mitigation of subjective feelings of jet lag, reduction of sleep onset latency, and contribution to sleep quality. Doses of melatonin for reaching these effects are between 0.5  and 5 mg. Moreover, the effects commented before can occur if the administration of the indolamine is close to bed time on the first day [52].
Melatonin were reported in seeds such as rice and sweet corn, besides roots, leaves and fruits from different plants. In fact, melatonin has been reported in strawberries, kiwis, pineapples, bananas and apples [24]. The presence of melatonin has also been described in olive oil, extra virgin olive oil, and in sunflower oil at concentrations between 71 and 113 pg mL −1 [53]. Other foods from Mediterranean diet that have sown high concentration of melatonin are salmon (3.7 ng g −1 ), chicken and lamb (2.3 ng g −1 and 1.6 ng g −1 respectively), bread's crumb and crust (341 and 138 pg g −1 respectively) and yogurt (126 pg g −1 ) [54,55]. Recently, other authors have reported melatonin in higher concentration than observed in previous reports (245-423 ng mL −1 ). Rodríguez-Naranjo et al. carried out an investigation in 10 monovarietal wines: Cabernet Sauvignon, Petit Verdot, Prieto Picudo, Syrah and Tempranillo [58]. Despite not found in grapes and musts, melatonin and its isomers were found in finished wines derived from them. That fact, revealed that melatonin is formed during wine processing from yeasts.
Melatonin can exert diverse beneficial effects for health, having demonstrated antioxidant, anticancer, immunomodulation and neuroprotective capacity [24]. In addition, biological activities of the most important metabolites of melatonin, N-1-Acetyl-N-2-formyl-5methoxykynuramine (AFMK) and N-1-Acetyl-5-methoxykynuramine (AMK), have also been reported. AFMK is a potent antioxidant, which provides protection to the DNA molecule and lipids through different many metabolic pathways. On the other hand, AMK is also a powerful antioxidant and is able to inhibit the biosynthesis of prostaglandins by binding to diazepam receptors [59][60][61].
Like other secondary metabolites, melatonin can stimulate endogenous antioxidant enzymes and/or capture free radicals (antioxidant capacity in vitro and in vivo) [47,62,63]. This neurohormone is capable of capturing reactive oxygen species, such as peroxynitrite [64]; or hydrogen peroxide in a dose-dependent manner [61]. In addition, melatonin has demonstrated antioxidant capacity in vitro by the ABTS + method [62]. In vivo studies have also demonstrated the antioxidant effect of melatonin. When administered in mice, it was observed that melatonin is able to reduce chronic oxidative stress related to aging [65], and that it could even reduce blood pressure in men with chronic hypertension [66].
The amphipathic nature of the molecule allows it to cross physiological barriers, so its presence has been described in the nucleus of the cytosol, in the mitochondria and in different biological membranes [67]. The importance of this fact lies in the fact that the molecule can act in the places where free radicals are formed, providing antioxidant defense from oxidative injury where they are needed.
The role of melatonin as neuroprotective agent is relevant. It has been successfully proved in sleep disorders, helping to restore circadian rhythm. Moreover, melatonin is especially effective in patients with neurodegenerative diseases [68]. Several scientific studies have been carried out with the aim for palliating consequences of diseases such as Alzheimer, Parkinson, Huntington disease or amyotrophic lateral sclerosis, obtaining satisfactory results [24].
The different effects of melatonin that could be useful for the improvement of neurological pathologies are large [69]. Melatonin can improve the evolution of Parkinson disease by the reduction of excitotoxicity caused by the autoxidation of dopamine [70], or improving quality and length of sleep [72]. Moreover, melatonin protects from injury to mitochondria, decreasing lipid peroxidation in multiple sclerosis and Alzheimer disease [73][74][75] and increase antioxidant enzymes generation [74]. Melatonin has also showed capacity to protect against cognitive deficits and inhibits formation of nicotinamide and Aβ plaque [76][77][78]. Melatonin also is able to reduce oxidative injury by reducing carbonyls formation [79,80], and delays the progression of amyotrophic lateral sclerosis by inhibiting MT1 reception loss [81].
Wine has proven to be another important source of hydroxytyrosol in the Mediterranean diet, and is formed in wine from tyrosol during alcoholic fermentation. Hydroxytyrosol was firstly found in Italian wines by Di Tommaso et al. [83], and later in other Italian and Greek wines [84][85][86]. Some authors describe a higher concentration in red wines (3.66-4.20 mg L −1 ) than in white wines (1.72-1.92 mg L −1 ) [24,87]. Finally, Minuti et al. obtained hydroxytyrosol concentrations between 1.8 and 3.1 mg L −1 in red wine [87]. Thus, scientific literature shows that wine is an important source of hydroxytyrosol in the diet, along with olive oil [24].
De La Torre et al. and Schröder et al. investigated the bioavailability of hydroxytyrosol by comparing the intake of red wine and olive oil [87][88][89]. The intake of red wine (250 mL) increased plasmatic concentration of hydroxytyrosol above 8 ng mL −1 , representing greater increase than the observed after the intake of olive oil (0.35 mg of hydroxytyrosol with the intake of wine red and 1.7 mg with the ingestion of olive oil). These authors proposed the endogenous production of hydroxytyrosol from ethanol and dopamine in response to the observed increase.
Moreover, tyramine has been proposed as another route for hydroxytyrosol formation, and could be partly responsible for the increased endogenous formation of hydroxytyrosol after the intake of red wine. Therefore, substantial content of tyramine in red wine, could lead to the increase of endogenous formation of hydroxytyrosol. However, the amount of tyramine in the red wine is not large enough to explain such increase in endogenous hydroxytyrosol [88].
Several studies have reported beneficial effects of hydroxytyrosol, mainly after the intake of olive oil (the main source of hydroxytyrosol in the Mediterranean diet). The different effects attributed to hydroxytyrosol include: antioxidant capacity, cardioprotective effect, anticancer, antimicrobial, neuroprotective and antidiabetic activity [24]. Numerous authors have proved their ability both to chelate oxidizing compounds [90,91], and to increase the concentration of antioxidant enzymes [91].
Neurodegenerative diseases, such as Alzheimer's disease or Parkinson's disease, could also be improved by the ingestion of hydroxytyrosol [92,93]. As melatonin, hydroxytyrosol has the ability to cross the blood-brain barrier. Therefore, it can go through the brain and is rapidly metabolized, acting where the oxidative attack is produced [24].
Different studies evaluating the effects of hydroxytyrosol, showed the great neuroprotective capacity of the molecule. Hydroxytyrosol considerably inhibits LDL efflux in a dose-dependant way, both in vivo and in vitro. That fact offers an initial knowledge for more studies as potential effects of hydroxytyrosol as neuroprotective compound [93]. Marhuenda et al. reported a descend on the formation of neuroprostanes and F 2 -dihomo-isoprostanes after the intake of red wine [28]. These effect was related to the content on hydroxytyrosol, more than other compounds from red wine matrix. Moreover, an oleuropein-enriched extract showed neuroprotective capacity by establishing a non-covalent complex with the amyloid-β-peptide, so can be decisive in many neurodegenerative diseases as Alzheimer's or Parkinson's disease. Therefore, hydroxytyrosol, being the main degradation molecule from oleuropein, can be proposed as a promising neuroprotective compound [92].
Polyphenols can induce antioxidant enzymes such as glutathione peroxidase, catalase and superoxide dismutase that decompose hydroperoxides, hydrogen peroxide and superoxide anions, respectively. Moreover, they can also inhibit the expression of enzymes such as xanthine oxidase [95]. Dietary polyphenols have been shown to play important roles in human health. In fact, high intake of fruits, vegetables and whole grains, which are rich in polyphenols, has been related to reduced risk of many chronic diseases including cancer, cardiovascular disease, chronic inflammation and many degenerative diseases [96].
Health benefits of catechins and proanthocyanidins are related to their antioxidant character and free radical scavenger activity. Moreover, they can switch mechanisms involved in different pathologies such as: hypertension, inflammation, proliferation cellular, thrombogenesis, hypertriglycemia, hypercholesterolemia and neurodegenerative diseases or neuroinflammation [94].
Studies conducted on cell cultures stimulated with lipopolysaccharide show that the administration of quercetin, catechin and epigallocatechin gallate blocks the inflammatory response by inhibiting NOSi and the expression of cyclooxygenase (COX-2), as well as the production of NO, the release of pro-inflammatory cytokines, and the generation of ROS, in astrocytes and in microglia [97]. These extracts of phytochemicals have also been shown to inhibit MAPKs such as p38 or ERK1/2, which regulate NOSi and TNF-α, in addition to the activation of glial cells [97]. Mendel et al. suggest that catechins, may protect brain from aging and reduce the incidence of dementia, Alzheimer disease and Parkinson disease [98]. Moreover, Geiser et al. indicate that both anti-aggregation and antioxidant characteristics of catechins may alter mRNA expression to reduce feed-forward mechanisms and promote non-amyloidogenic processing [99].
In vivo studies show that chronic administration of epicatechin in combination with physical exercise, improves spatial memory, due to the increase in the Akt protein that activates the endothelial nitric oxide synthase (NOSe) enzyme, stimulate the angiogenesis, as well as the increase in neuronal density in regions such as the dentate gyrus of the hippocampus [100].
Other group of polyphenols which has showed several benefits are anthocyanins. Several studies have shown beneficial effects of anthocyanins on health, and the high antioxidant capacity due to their capacity to protect from free radicals by the donation of hydrogen atoms. The role of anthocyanins in neurodegenerative diseases is strongly linked to oxidative attack protection. Anthocyanins can modulate cognitive and motor function, enhancing memory, and preventing age-related decline in neural function [102]. Extracts rich in anthocyanins and proanthocyanidins exhibited greater neuroprotective activity than extracts rich in other polyphenols. Moreover, many individual anthocyanins interfered with rotenone neurotoxicity, which can be related with increased memory [103].
Finally, mayor food containing anthocyanins are berries that can effectively reverse agerelated deficits in certain aspects of working memory. Anthocyanins and other flavonoids can prevent neuroinflammation, by the activation of synaptic signaling, and improving blood flow to the brain. It appears that some dietary anthocyanins can cross the blood-brain barrier, allowing the compounds to have a direct beneficial effect [100]. Anthocyanins suppress mitochondrial oxidative stress-induced apoptosis by preserving mitochondrial GSH and inhibiting cardiolipin oxidation and mitochondrial fragmentation [104].

Conclusion
Neurodegenerative diseases are a public health problem and the possibilities of delaying their evolution constitute a challenge for research. Considering the relationship between oxidative stress and neuroinflammation with neurodegenerative diseases, monitoring a diet rich in bioactive substances with antioxidant activity and polyunsaturated fatty acids of the omega-3 series, with a proven antiinflammatory and neuroprotective effect, could slow down the evolution of the disease, improve cognitive deterioration, delay the decline of motor symptoms and improve the quality of life of patients. An example of this type of diet is the Mediterranean diet, which is characterized by the consumption of fruits, vegetables, legumes, nuts, olive oil, moderate consumption of red wine and blue fish that incorporate bioactive substances with beneficial effects on health.