Role of the Mediterranean Diet in the Brain and Neurodegenerative Diseases

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Chapter 1

Effects of Mediterranean Diet Components on Neurodegenerative Diseases

Akhlaq A. Farooqui¹ and Tahira Farooqui²,    ¹Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, OH, United States,    ²Department of Entomology, The Ohio State University, Columbus, OH, United States

Abstract

Consumption of Mediterranean diet not only contributes to significant improvements in health status, but also delays the onset of chronic visceral and neurodegenerative diseases. The Mediterranean diet is characterized by a high intake of fresh fruits, vegetables, legumes, and whole grains, moderate to high intake of fish; a low intake of saturated lipids and high intake of olive oil, low intake of meat, and a modest intake of red wine. Mediterranean diet not only increases longevity by lowering cardiovascular disease, inhibiting cancer growth, but also by protecting the body from age-dependent cognitive decline. Studies on beneficial effects of Mediterranean pattern on human population have been controversial. However, it is becoming increasingly evident that long-term, double blind and randomized controlled trials on large human population are needed to know the beneficial effects of Mediterranean diet on human population.

Keywords

Mediterranean diet; vegetables and fruits; olive oil; resveratrol; docosahexaenoic acid; S-allyl-L-cysteine; allicin; oxidative stress; neuroinflammation

Introduction

Diet consumed in Mediterranean area (e.g., Italy, Spain, Greece, and Turkey) is called as Mediterranean diet. Components of Mediterranean diet include vegetables, legumes, fruits, whole grains, fish, olive oil, fresh garlic, low levels of dairy products (cheese and yogurt), nuts, and modest intake of red wine (Fig. 1.1).¹ Fruits and vegetables are enriched in vitamins, carotenoids, flavonoids, fiber, potassium, magnesium, and other minerals. These components prevent age-related neurologic dysfunction not only by preventing free radical damage and neuroinflammation but also by protecting the body from age-dependent cognitive decline and increasing longevity (Fig. 1.1).¹,² Less information is available on the synergistic effects of various components of Mediterranean diet.³ A number of recent cross-sectional and prospective studies have attempted to gain further insight into the relationship between adherence to the overall Mediterranean diet pattern and age-related cognitive function.⁴,⁵ Thus Mediterranean diet has been reported to significantly decrease cognitive dysfunction and mortality in 182 men and women aged 70 years.⁶ This study has been recently extended to larger population in Greece (more than 22,000 adults) displaying a significant reduction in total mortality with greater adherence to the traditional Mediterranean diet.⁶ Recently meta-analysis of several studies has indicated that greater adherence to a Mediterranean-style diet not only contributes to longevity, but also shows reduction in risk for cardiovascular mortality and cancer incidences.⁷ These findings are promising. However, the results on cognitive function have been inconsistent. Some studies report a significant association between the Mediterranean diet consumption and age-related cognitive function,⁴,⁵,⁸ and others reveal no link.⁸–¹⁰ The individual components of the Mediterranean diet (tyrosol, hydroxytyrosol, oleocanthal, resveratrol, alliin, and docosahexaenoic and eicosapentaenoic acids) produce beneficial effects in human and animal models of chronic and acute neurological disorders such as Alzheimer disease (AD), Parkinson disease (PD), Huntington disease (HD), amyotrophic lateral sclerosis (ALS) and stroke by inhibiting oxidative stress, neuroinflammation, normalizing mitochondrial dysfunction, improving endothelial function, and increasing cognitive function.² Although the above mentioned neurodegenerative diseases have different clinical and pathological features, the signal transduction mechanisms at the molecular level appear to overlap considerably.²,¹¹ In several neurodegenerative diseases, the accumulation of proteins (typically, beta-amyloid (Aβ) in AD, and alpha-synuclein (α-S) in PD, mutated huntingtin in HD, and mutated Cu/Zn-superoxide dismutase, SOD, in ALS) misfolds and self-assembles via a nucleated-growth mechanism to form transient, low-molecular-weight soluble oligomers, later converting into β-sheet-rich protofibrils and finally stabilizes as highly ordered fibrillar structures. The shared mechanism of an aberrant conversion of the native, nontoxic structure of a protein into toxic aggregates, hence, classifies most neurodegenerative diseases as protein misfolding disorders.¹²

Figure 1.1 Effect of long-term consumption of Mediterranean diet components on quality of life and life expectancy.

Long-term consumption of Mediterranean diet not only decreases oxidative stress and neuroinflammation in neurodegenerative diseases (Fig. 1.1), but also results in the increase in longevity through maintenance of the telomeres length and prevention of brain atrophy.¹³–¹⁵ Telomeres are essential and dynamic regulators of cellular life span and chromosome integrity in eukaryocyte. They are composed of guanine-rich sequence-TTAGGG. Each cell division is accompanied by shortening of telomeres into replicative senescence, which becomes susceptible to apoptosis when exposed to increased oxidative stress.¹⁶ DNA telomere length is maintained mainly by telomerase, and regulated by proinflammation cytokines and oxidative stress.¹⁶,¹⁷ Significant information has been published on beneficial effects of components of Mediterranean diet such as fish oil, olive oil, red wine pigment (resveratrol), garlic, and green and colored vegetables and fruits on brain. The purpose of this chapter is to provide information on molecular mechanism of beneficial effects of various components of Mediterranean diet and Mediterranean diet pattern not only on normal aging brain, but also in patients and animal models of neurodegenerative diseases.

Beneficial Effects of Fresh Vegetables and Fruits on the Brain

Long-term consumption of diet enriched in fresh vegetables and fruits in Mediterranean diet not only protects brain from acute and chronic neurological diseases, but also produces beneficial effects in a number of chronic visceral diseases, such as cancer, diabetes, and heart disease. These beneficial effects are not only due to the presence of antioxidants (α-tocopherol, ascorbic acid, and β-carotene), but also due to the effects of flavonoids (polyphenols and anthocyanins), which are present in fresh vegetable and fruits.¹⁸ Components of vegetables and fruits have been reported to modulate polyol pathway leading to the reduction in the development and intensity of oxidative stress, and consequently the development of diabetic complications. Furthermore, polyphenols (flavonoids, phenolic acids, proanthocyanidins, and tannins), which are present in vegetables and fruits, have been reported to alter glycemia by inhibiting carbohydrate digestion, reducing carbohydrate absorption in the intestines, stimulating the release of insulin from pancreatic β-cells, and modulating hepatic glucose output.¹⁹,²⁰ Vegetable and fruits contain soluble and insoluble fibers, which affect intestinal tract time, absorption of macronutrients, alter the action of digestive enzymes and secretion of gastrointestinal and pancreatic hormones.²¹ Insoluble fiber can decrease intestinal tract time, potentially reducing time for the carbohydrates to be absorbed in the jejunum.²² Soluble fiber delays gastric emptying by slowing the absorption and digestion of carbohydrates potentially delaying the insulin response.²² In addition, nondigestive fiber is fermented by the microflora of the colon to produce short chain fatty acids. The production of short chain fatty acids also impacts on carbohydrate metabolism.²³ Among vegetables, cruciferous vegetables such as broccoli, Brussels sprouts, cabbage, kale, and cauliflower contain isothiocyanates and indole-3-carbinol, which have been reported to produce anticancer effects. Vegetables and fruits contain high amounts of magnesium, potassium, and nitrate. These ions produce beneficial effects not only on circulatory system, but also on the brain and visceral tissues. Thus dietary magnesium regulates many kinases including tyrosine kinase, but also magnesium-dependent ATPase, and enzymes of glycolytic pathways. Tyrosine kinase is a component of the beta subunit of the insulin receptor. It increases insulin sensitivity by promoting translocation of GLUT4 leading to the uptake of glucose into the cell (Fig. 1.2). In addition, magnesium not only modulates vascular tone and responsiveness, but also influences acetylcholine-induced endothelium-dependent relaxation. Magnesium can also act by stabilizing cell membranes and functions as a signal transducer supporting the view that magnesium contributes to the protection of neuronal cell membranes and modulates neurotransmitters release in the brain.²⁴ Accumulating evidence also suggests that magnesium is a cofactor for more than 300 enzymes associated with glucose metabolism, protein synthesis, cellular energy production and storage, DNA and RNA synthesis, and stabilization of mitochondrial membranes.

Figure 1.2 Effect of long-term consumption of Mediterranean diet on nitric oxide and magnesium-mediated processes.

Potassium enters neural membranes through potassium channels and plays important roles in cell volume regulation, hormone secretion, synaptic transmission, and muscle contraction. The K+ channels are a superfamily of diverse channels involved in potassium currents in visceral and brain tissues. On the basis of their structure, the K+ channels are categorized into voltage-gated K+ channel (Kv), inward rectifying K+ channel (Kir), and two-pore domain K+ channel (K2P) families.²⁵ Location of K+ channels within specialized neuronal compartments and astrocytes defines their physiological role in the brain tissue. This localization also impacts their activity, due to localized exposure to diverse cellular determinants of channel function. Recent studies in mammalian brain reveal an exquisite refinement of K+ subcellular localization. This includes axonal potassium at the initial segment, and near/within nodes of Ranvier and presynaptic terminals.²⁶ The presence of dendritic K+ channels at various sites reflects specific synaptic input, and K+ transport defining novel neuronal compartments. This indicates diversity of potassium entry and K+ channels onto the complex architecture of mammalian neurons painting a complex picture of electrical signal processing in individual neuronal compartments, and ultimately neurotransmission and behavior.²⁶

Nitrate, which is present in vegetables and fruits, is metabolized into nitrite and nitric oxide. It not only improves endothelial function and reduces blood pressure, but also increases regional perfusion in the brain. Recent studies have indicated that dietary nitrate promotes cognitive performance and prefrontal cortex cerebral blood flow (CBF) parameters in healthy adults supporting the view that dietary nitrate can produce beneficial effects on brain function (Fig. 1.2).²⁷,²⁸ The supplementation of nitrate also improves exercise performance. Inclusion of nitrate in diet also produces beneficial effects on vascular functions by reducing blood pressure, inhibiting platelet aggregation, and preserving or improving endothelial dysfunction, enhancing exercise performance in healthy individuals and patients with peripheral arterial disease.²⁹

Beneficial Effects of Olive Oil on the Brain

Extra virgin olive oil contains approximately 36 phenolic compounds including tyrosol, hydroxytyrosols, oleocanthal, and oleuropein and carotenes (Fig. 1.3). These phenolic compounds enter brain and produce neuroprotective effects through their antioxidant, antiapoptotic, and antiinflammatory activities. Based on detailed investigations, it is suggested that hydroxytyrosol acts as a scavenger of reactive free radicals leading to neuroprotective effects on neural cells during oxidative stress.³⁰,³¹ Moreover, hydroxytyrosol not only induces the expression of antioxidant enzymes through the activation of transcription factor Nrf2, but may also act by reducing the expression of cell adhesion molecules,³² inhibiting platelet aggregation,³³ and exerting antiinflammatory effects.³⁴,³⁵

Figure 1.3 Chemical structures of components of Mediterranean diet.

Oleuropein and oleocanthal have been reported to interfere with the amyloid aggregation of Aβ, amylin, and Tau (Fig. 1.4). The latter is a microtubule-associated protein found aggregated in several tauopathies, including AD. The data reported indicate that oleuropein³⁶,³⁷ and oleocanthal³⁸,³⁹ interfere with the aggregation path of these peptides/proteins upon binding to the aggregating molecules, skipping the appearance of toxic species and favoring the formation of nontoxic disordered aggregates.

Figure 1.4 Effects of Mediterranean diet components on oxidative stress, neuroinflammation, beta-amyloid generation along with related signal transduction processes.

PtdCho, Phosphatidylcholine; ARA, arachidonic acid; cPLA2, cytosolic phospholipase A2; COX-2, cyclooxygenase-2; ROS, reactive oxygen species; NF-κB, nuclear factor kappaB; NF-κB-RE, nuclear factor κB-response element; IκB, inhibitory subunit of NF-κB; IκB-P, phosphorylated IκB; TNF-α, tumor necrosis factor-α; IL-1β, interleukin-1β; IL-6, interleukin-6; APP, amyloid precursor protein; Aβ42, beta-amyloid; iNOS, superoxide; Nrf2, NFE2-related factor 2; HO-1, heme oxygenase-1; NADH quinine oxidoreductase; γ-GCL, γ-glutamylcystein ligase; iNOS, inducible nitric oxide synthase; NO, nitric oxide; ONOO–, peroxynitrite.

Oleocanthal not only inhibits cyclooxygenase (COX), but also induces antioxidant effects in the brain.⁴⁰–⁴² Treatment of mice with oleocanthal for 4 weeks significantly reduces Aβ load in the hippocampal parenchyma and microvessels.⁴⁰,⁴² Reduction in Aβ levels may be due to the increase in cerebral clearance of Aβ across the blood–brain barrier (BBB). Furthermore, oleocanthal may also act by increasing the expression of Aβ clearance proteins (P-glycoprotein and LRP1) at the BBB as well as by activating the ApoE-dependent amyloid clearance pathway in the mice brains.⁴⁰,⁴² The antiinflammatory effect of oleocanthal in the brains of TgSwDI mice also reduces astrocytes activation leading to a decrease in levels of IL-1β, a cytokine, which contributes to neuroinflammation. Oleocanthal also inhibits the fibrillization of both Aβ40 and Aβ42 in vitro.⁴³ It is also suggested that oleocanthal also protects neurons from Aβ-induced synaptic deterioration and oxidative stress.⁴³ It is also reported that oleocanthal is homologous with the nonsteroidal antiinflammatory drug (NSAID) ibuprofen for both perceptual and antiinflammatory properties.⁴¹ Ibuprofen is known to exert beneficial effects on markers of neurodegenerative disease.⁴⁴ It is also reported that oleocanthal inhibits tau fibrillization in vitro by forming an adduct with PHF6 peptide. PHF6 is a VQIXXK motif that resides in the microtubule binding region.⁴⁵ Converging evidence suggests that components of olive oil affect both Aβ as well as tau fibrillization. No information is available on the effect of olive oil on PD, HD, and ALS. However, in 3-nitropropionic acid administered model of HD, olive oil reduces lipid peroxidation product levels and blocks the GSH depletion caused by 3-nitropropionic acid in both striatum and rest of the brain in Wistar rats.⁴⁶ In addition, olive oil blocks and reverses the effect of 3-nitropropionic acid on succinate dehydrogenase activity supporting the view that olive oil acts as an antioxidant in this animal model.⁴⁶,⁴⁷

Beneficial Effects of Resveratrol on the Brain

Resveratrol (3,5,4′-trihydroxystilbene) is a nonflavonoids polyphenolic compound produced in a variety of plants (red grapes, mulberries, raspberries, blueberries, plums, apples, peanuts, red wines, and tea) in response to pathogen attack or under stress conditions such as UV radiation and exposure to heavy metal ions (Fig. 1.3).⁴⁸ It occurs in two isoforms: trans-resveratrol, the more stable form, and cis-resveratrol, which is less stable. Both forms are produced by phenylpropanoid pathway. Resveratrol not only produces cardioprotective, anticancer, antiinflammatory, and antioxidant properties, but also increases lifespan of yeast, worms, flies, and rodents,⁴⁹ by stimulating sirtuin (SIRT) proteins, NAD+-dependent de-acetylase involved in the regulation of metabolism, apoptosis, mitochondrial biogenesis, inflammation, fatty acid metabolism, and glucose homeostasis.⁵⁰,⁵¹ Studies on the effect of resveratrol in animal models of neurotraumatic and neurodegenerative diseases have indicated that molecular mechanisms of resveratrol neuroprotective actions can be due to (1) antiinflammatory and antioxidant effects, including free radical scavenging and metal chelation; (2) modulation of cell signaling pathways; and (3) antiamyloid action through direct binding with specific accumulating proteins such as Aβ, αS, and Tau (Fig. 1.4). This wide mode of action highlights a key aspect from studies on natural polyphenols,¹,⁵² including wine polyphenols—namely that exhibit a remarkable ability to simultaneously and synergistically modulate multiple molecular targets, suggesting a greater potential for therapeutic efficacy in the complex pathogenesis of AD and PD.⁵³

Among polyphenols, resveratrol produces beneficial effects not only due to antioxidant and free radical scavenging activities but also through antiaging and antiinflammatory effects. The mechanisms by which resveratrol attenuates neuroinflammation are not completely clear yet. A major pathway seems to involve sirtuin-dependent arrest of NFκB-light-chain-enhancer of activated B cells signaling cascades, a step that results in downstream blockade of microglia activation.⁵⁴ Due to the presence of hydroxyl groups, resveratrol has ability to transfer hydrogen atoms or electrons to the free radicals according to the following reaction:

Antiaging and antiinflammatory effects of resveratrol may be related to the activation of heme oxygenase, whereas antiinflammatory properties of resveratrol may be due to the inhibition of microglial cell activation, inhibition of NF-κB activation, and decrease in the expression of TNF-α and IL-1β. It is also reported that resveratrol-treated animals show increase in net neurogenesis and microvasculature, and diminished astrocyte hypertrophy and microglial activation in the hippocampus.⁵⁵ These observations suggest that resveratrol treatment in late middle age is efficacious not only in improving memory, but also mood function in old age. Modulation of the hippocampus plasticity and suppression of chronic low-level inflammation appear to underlie the functional benefits mediated by resveratrol.⁵⁶ In animal models of AD and PD, resveratrol not only decreases levels of secreted and intracellular Aβ peptides and α-synuclein, but also increases the blood flow.⁵⁷ Resveratrol also promotes intracellular degradation of Aβ through a mechanism involving the proteasome activity.⁵⁸ In the Tg2576 mouse model of AD, moderate consumption of Cabernet Sauvignon, a red wine enriched in resveratrol, stimulates nonamyloidogenic α-secretase-mediated amyloid precursor protein (APP) processing leading to neuroprotection and preventing the generation of amyloidogenic Aß42-mediated cognitive deterioration.⁵⁹ Resveratrol potently inhibits polymerization of the β-amyloid peptide⁶⁰ by a mechanism that does not involve β-amyloid production because resveratrol has no effect on the activity of β- and γ-secretases but stimulates indirectly the proteosomal degradation of β-amyloid peptides.⁵⁸

Converging evidence suggests that at low doses, phytochemicals (resveratrol, allicin, oleuropein, and oleocanthal) present in Mediterranean diet produce beneficial effects in humans, whereas in high amounts they mediate toxic effects. This process is referred as hormesis.⁶¹–⁶³ These phytochemicals activate adaptive stress response signaling pathways that increase cellular resistance to injury and disease.⁶² Also, these phytochemicals fruits, vegetables, and nuts are generally well-tolerated by the human body. Furthermore, these compounds can cross the BBB and produce neuroprotective stress response pathways at low concentrations.¹

Epidemiological studies have indicated that high consumption of Mediterranean diet components is inversely associated with risk of PD and HD.⁶⁴ The accumulation of misfolded α-S in dopaminergic neurons is closely associated with the pathogenesis of PD. Resveratrol exerts a wide range of beneficial effects via the activation of sirtuin 1 (SIRT1) and the induction of vitagenes. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced mouse model of PD, resveratrol ameliorates both motor deficits and pathological changes in MPTP-treated mice via the activation of SIRT1 and the subsequent LC3 deacetylation-mediated autophagic degradation of α-S supporting the view that this component of Mediterranean diet may produce potential prophylactic and/or therapeutic effects in PD.⁶⁵ In a fly model of PD, the expression of human α-S components of red wine prevents α-S aggregation leading to the modification in fly behavior.⁶⁶ Polyphenols in red wine also inhibit the formation of fibrillar α-S and destabilize fibrillar α-S in a dose-dependent manner.⁶⁷ These studies further support the view that polyphenols (resveratrol) may protect neurons in animal models of PD

Cellular mechanisms involved in neurodegeneration in HD remain unknown. It is becoming increasingly evident that defects in energy metabolism, particularly mitochondrial function, represent an important mechanism for HD pathogenesis in humans and animal models. In 3-nitropropionic acid model of HD, repeated treatment with resveratrol (5 and 10 mg/kg, orally), once daily for a period of 8 days beginning 4 days prior to 3-nitropropionic acid administration, significantly improves the 3-nitropropionic acid-mediated motor and cognitive impairment. Biochemical analysis has indicated that systemic 3-nitropropionic acid administration not only significantly increases lipid peroxidation and nitrite levels, but also depletes reduced glutathione levels and decreases succinate dehydrogenase activity in the brains of rats supporting the view that resveratrol significantly reverses 3-nitropropionic acid-induced motor and cognitive impairment, and that the beneficial effects of resveratrol can be attributed to its antioxidant activity.⁴⁷ An important point with regard to red wine drinking is that light-to-moderate drinking (one to three drinks per day) significantly lowers the risk of any dementia and vascular dementia in individuals of 55 years and over.⁶⁸ Similarly, other studies have indicated that chances for dementia among older adults, whose weekly alcohol consumption was one to six drinks every week, regardless of the type of beverage consumed were lower than alcohol abstainers.⁶⁹

Oxidative stress and neuroinflammation also contribute to the pathogenesis of ALS. Components of Mediterranean diet such as tyrosol, hydroxytyrosol, and resveratrol not only act as antioxidants, but also stimulate Nrf2, a transcription factor that contributes to neural cell survival not only in animal models of ALS, but also in animal models of AD, PD, and HD. Thus, under physiological conditions, Keap1 and Nrf2 complex resides in the cytoplasm. Following induction of oxidative stress, Nrf2 translocates from the cytoplasm into the nucleus where it forms heterodimers with other transcription factors such as Maf, or c-Jun and interacts with antioxidant response elements (AREs). This ARE–Nrf2 binding leads to activation of the Keap1–Nrf2 pathway, which induces the expression of over 100 cytoprotective genes. These genes include (1) the cellular antioxidant and antiinflammatory defense enzymes such as NAD(P)H quinone oxyreductase (NQO1), and genes modulating levels of glutathione; (2) enzymes of glutathione biosynthesis, extracellular SOD, and glutamate-6-phosphate dehydrogenase; and (3) Pro- and antiinflammatory enzymes such as cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and heme oxygenase-1 (HO-1). In addition, Nrf2 activation also produces the expression of genes that regulate mitochondrial biogenesis and glycolytic metabolism, angiogenesis, cell survival, apoptosis, and other processes that interfere with cell survival.⁷⁰,⁷¹ Upon the recovery of cellular redox homeostasis, Keap1 travels into the nucleus to dissociate Nrf2 from the ARE. Subsequently, the Nrf2–Keap1 complex is transported out of the nucleus terminating the Nrf2/ARE signaling pathway.⁷⁰,⁷¹

Beneficial Effects of Garlic Components on the Brain

Garlic (Allium sativum) is an important component of Mediterranean diet. It contains several organosulfur compounds, such as allicin, alliin, diallyl sulfide, diallyl disulfide, diallyl trisulfide, S-allylcysteine (SAC), dithiins, ajoene, methyl allyl disulfide, methyl allyl trisulfide, 2-vinyl-1,3-dithiin, and 3-vinyl-1,2-dithiin.⁷² These are lipophilic thioesters derived from oxidized allicin, which are synthesized when garlic cloves are crushed. Garlic preparations induce their effects via different antioxidant mechanisms such as their ability to (1) scavenge reactive oxygen species (ROS) and reactive nitrogen species (RNS), (2) increase enzymic and nonenzymic antioxidants levels, and (3) inhibit some prooxidant enzymes (xanthine oxidase, COX, and NADPH oxidase). Neurochemical actions of garlic effects are induced through the modulation of transcription factors such as NF-κB and Nrf2 (Fig. 1.4). Thus the inhibition of NF-κB by garlic components retards the expression of proinflammatory cytokines (TNF-α, IL-1β, and IL-6). Organosulfur compounds from garlic not only promote the migration of NF-κB to the nucleus, but also inhibit 5-lipoxygenase (5-LOX), the enzyme, which transforms arachidonic acid into leukotrienes.¹ Some garlic components also activate Nrf2 and promote the expression of antiinflammatory defense enzymes. Most studies on the effects of garlic components in neurological disorders have been performed in animal and cell culture models. Thus, S-allyl-L-cysteine (SAC) is the most active component of aged garlic extract (AGE). SAC lowers Aβ levels and toxicity.⁷³ Treatment of neuronal cultures with AGE and SAC protects against H2O2-mediated oxidative stress the associated protein of 25 kDa (SNAP25) from ROS-mediated insult. In vitro studies have also indicated that SAC has ability to block Aβ fibrillation through the destabilization of Aβ fibrils.⁷⁴ SAC reduces the brain levels of Aβ40 and Aβ42, lowers APP level, and downregulates BACE1 expressions resulting in lower Aβ accumulation and reduced levels of advanced glycation end products (carboxymethyllysine and pentosidine).⁷⁴ Nothing is known about the effect of garlic on PD, HD, and ALS patients. However, in 6-hydroxydopamine (6-OHDA) induced model of PD in PC12 cells, allicin produces significant increase in cell viability, and decreases LDH release and apoptotic cell death after 6-OHDA exposure.⁷⁵ Allicin also inhibits ROS generation, reduces lipid peroxidation, and preserves the endogenous antioxidant enzyme activities suggesting that the protective effects of allicin may not only be caused by the suppression of mitochondrial dysfunction, but also due to the enhancement of mitochondrial biogenesis and prevention of fragmentation of mitochondrial network after 6-OHDA treatment.⁷⁵

Beneficial Effects of Fish Consumption and Fish Oil on the Brain

Another important component of Mediterranean diet is fish, which contains high levels of n-3 or ω-3 fatty acids (docosahexenoic acid, DHA (22:6n3) and eicosapentaenoic acid, EPA (20:5n3)). DHA is the most abundant n-3 fatty acid in the brain. DHA and EPA promote the formation of lipid rafts. Like other components of Mediterranean diet, these fatty acids produce beneficial effects on neurodegenerative diseases,⁷⁶ not only due to their effect on physicochemical properties of neural membrane (such as acyl chain order, permeability, fluidity, and synaptic connectivity), but also through the generation of n-3 fatty acid-derived docosanoids (resolvins, neuroprotectins, and maresins). These mediators produce antioxidant, antiinflammatory, and antiapoptotic effects and protect neuronal cells from neurodegeneration.² Studies with aged rodents have consistently shown that n-3 fatty acids supplementation improves neurogenesis and synaptogenesis, executive functions, and learning abilities, while n-3 PUFA deficiency is associated with memory deficits and impaired hippocampal plasticity.⁵⁵,⁷⁷,⁷⁸ Epidemiological studies have indicated that sufficient DHA intake reduces the risk of developing neurodegenerative diseases.⁷⁶,⁷⁹,⁸⁰ In addition, the consumption of fish and fish oil has been reported to reduce cognitive decline.⁷⁶ A recent trial of fish oil has indicated positive effects of DHA supplementation on cognition in patients with very mild AD.⁸¹ Similarly, investigations on three different transgenic models of AD indicate that animal models of AD are more vulnerable to DHA depletion than controls and that DHA exerts a beneficial effect against pathological signs of AD, including Aβ accumulation, cognitive impairment, synaptic marker loss, and hyperphosphorylation of Tau.⁸²,⁸³ Studies on the effects of DHA in MPTP-induced model of PD have indicated that DHA not only decreases the loss of dopaminergic neurons, but also diminishes the symptoms of PD.⁸⁴ In an animal model of ALS, EPA, an omega 3 fatty acid and precursor for DHA produces harmful effects in SOD1 mice. This is an unexpected finding. It is proposed that the treatment results in the enhancement of neuroinflammation, faster disease progression, and hastened death for SOD1 mice.⁸⁵ One explanation proposed by the authors is the greater susceptibility for PUFA to be peroxidized and therefore toxic.⁸⁶ Therefore the increase in DHA of spinal cord from ALS patients could favor lipid peroxidability and be potentially a toxic factor in ALS.⁸⁷

Collectively, the beneficial effects of the individual components of the Mediterranean diet (including tyrosol, hydroxytyrosol, oleocanthal, resveratrol, alliin, and docosahexaenoic and eicosapentaenoic acids) in human and animal models of chronic and acute neurological disorders (Table 1.1)⁴⁶,⁴⁷,⁵⁷,⁵⁸,⁶⁵,⁸⁸–⁹⁶ produce beneficial effects through their antioxidant, antiinflammatory, and vasodilatory activities. These activities may delay the onset of neurotraumatic and neurodegenerative diseases.

Table 1.1

Effects of Mediterranean Diet Components on Animal Models of Neurotraumatic and Neurodegenerative Diseases

Conclusion

Mediterranean diet is one of the best diet patterns associated with reduced risk for not only cardiovascular and neurodegenerative diseases, but also type 2 diabetes mellitus, and some types of cancer. This dietary pattern is characterized by long-term consumption of plant foods, cereals, legumes, fish, and olive oil as the main source of fat and moderate amount of red wine. The biological mechanisms for chronic disease prevention by a Mediterranean pattern are due to high amounts of antioxidants, polyphenols, and other compounds such as monounsaturated and polyunsaturated fatty acids that are present in Mediterranean diet. It is realized that the beneficial effects of Mediterranean pattern on human population have been controversial. However, recent studies suggest that more long-term, double blind and randomized controlled trials on large human population are needed to promote the consumption of Mediterranean diet. This may help in establishing whether improved adherence to this diet may help in preventing or delaying the onset of neurodegenerative diseases, dementia, type 2 diabetes, and some types of cancers.

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