Olive oil phenols and neuroprotection

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Olive oil is a rich source of phenolic components which have a wide variety of ... The beneficial effects of olive oil phenols attributed to a variety of biological ...
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Olive oil phenols and neuroprotection Ali Reza Khalatbary Anatomy Department, Mazandaran University of Medical Sciences, Sari, Iran Olive oil is a rich source of phenolic components which have a wide variety of beneficial health effects in vitro, in vivo, and clinically. The beneficial effects of olive oil phenols attributed to a variety of biological activities including free radical scavenging/antioxidant actions, anti-inflammatory effects, anti-carcinogenic properties, and anti-microbial activities. On the other hand, olive oil phenols have been shown to be some of neuroprotective effects against cerebral ischemia, spinal cord injury, Huntington’s disease, Alzheimer’s diseases, multiple sclerosis, Parkinson’s disease, aging, and peripheral neuropathy. This paper summarizes current knowledge on the mechanisms of neuroprotective effects of olive oil phenols. Keywords: Olive oil phenols, Oxidative stress, Neuroprotection, Neurodegenerative disease

Introduction Within the previous decades, a rapidly growing number of phenol compounds with neuroprotective effects have been described. One of the main sources of these molecules is olive oil, the principal source of fat in the Mediterranean diet.1 Large body of epidemiological evidence support the beneficial effects of the Mediterranean diet in human health, particularly in the lower incidence of atherosclerosis, cardiovascular disease, and certain cancer types.2–4 Meanwhile, particular emphasis has been placed on the benefits of this diet for counteracting certain neurodegenerative diseases. The beneficial effects have been partially linked to the regular intake of olive oil by Mediterranean populations, which to be in the range of 25–50 ml per day.5 The chief active components of olive oil include oleic acid, a monounsaturated fatty acid which is approximately 72%, phenolic constituents, which to be in the range of 196–500 mg/kg, and squalene, a triterpene hydrocarbon which is approximately 0.7%.5 Olive oil is a source of at least 30 phenolic compounds, which is divided into three categories: secoiridoids such as oleuropein (3,4-dihydroxyphenylelenolic acid) and oleocanthal (a deacetoxy ligstroside aglycone), simple phenols such as hydroxytyrosol (3,4-dihydroxyphenolethanol) and tyrosol (4-hydroxyphenylethanol), and lignans (estrogen-like chemicals).6,7 On the other hand, hydrolysis of oleuropein, which occurs during olive oil storage, results in the formation of hydroxytyrosol and Correspondence to: Ali Reza Khalatbary, Ph.D., Anatomy Department, Mazandaran University of Medical Sciences, P.O. Box: 4847191977, Sari, Iran. Email: [email protected]

© W. S. Maney & Son Ltd 2013 DOI 10.1179/1476830513Y.0000000052

tyrosol.8 Tyrosol is a mono-phenol; meanwhile oleuropein and hydroxytyrosol are catechols (1,2-dihydroxybenzene) with high concentration 50–800 mg/kg in olive oil.9 Hydroxytyrosol and oleuropein are orthodiphenols with two adjacent hydroxyl groups to the ring structure.7 Antioxidant properties of ortho-diphenols are related to hydrogen-donation by forming an intramolecular hydrogen bond between the free hydrogens of their hydroxyl group and their phenoxyl radicals.10 Furthermore, oleuropein prevents free radical formation through its ability to chelate metal ions such as Cu and Fe, which catalyze free radical generation reactions.11 There is accumulating evidence that attributed the beneficial effects of oleuropein and its derivatives such as hydroxytyrosole, to a variety of biological activities, including free radical scavenging/antioxidant, anti-inflammatory, anti-carcinogenic, anti-microbial, anti-atherogenic, and antiviral properties.2,12 In addition, olive oil phenols have been shown to be some of neuroprotective effects against brain hypoxia-reoxigenation,13,14 cerebral ischemia,15,16 brain damage after hypoxia-reoxygenation in diabetic rats,17 aging,18 Alzheimer’s diseases,19 Huntington’s disease,20 multiple sclerosis,21 Parkinson’s disease,22 peripheral neuropathy,23 and spinal cord injury.24,25 On the other hand, some findings suggested that olive oil has beneficial effects on learning and memory deficits found in aging by reversing oxidative damage in the brain.26 In this review, we have focused on neuroprotective effects of olive oil phenolic compounds and their molecular mechanisms responsible for the neuroprotection.

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Bioavailability of olive oil phenols Animal and human studies demonstrated that olive oil phenolic compounds are highly bioavailable, supporting their potential health-promoting properties. In this regard, one study showed that apparent in vivo absorption of the ingested olive oil phenols was more than 55–66 mol% in humans, confirmed by the excretion of tyrosol and hydroxytyrosol in urine.27 In other word, absorbed olive oil phenols are extensively modified in the body of human.28 In this regard, studies showed that of the total amount of ingested phenols, at least 5% was excreted in urine as tyrosol and hydroxytyrosol.7 Tyrosol and hydroxytyrosol rise early in urine after virgin olive oil ingestion reaching a peak at around 0–4 and 0–2 h, respectively.28,29 Meanwhile, results showed that approximately 98% of hydroxytyrosol is present in plasma and urine in conjugated forms, mainly glucuronoconjugates.29 Although the mechanism of absorption of olive oil phenols in unclear, but different mechanisms may account, including passive diffusion for tyrosol and hydroxytyrosol,30 and glucose transporter, transcellular passive diffusion or paracellular route for oleuropein-glycoside.31 However, there are no data available on the mechanisms of oleuropein and ligtroside-aglycones absorption. Furthermore, the first requirement for a dietary compound to be a potential in vivo antioxidant is that it enters the blood circulation. In this regard, it is well documented that hydroxytyrosol is able to cross the blood–brain barrier (BBB) in relatively large amounts.32 Also Bu et al. 15 found that tyrosol passed the BBB and showed the neuroprotective effect on transient focal cerebral ischemia in rats. Two studies showed that tyrosol and hydroytyrosol rise early after virgin olive oil ingestion reaching a peak at around 1 h in plasma.29,33 In addition, D’Angelo et al. 32 measured hydroxytyrosol in the rat brain 1 h after a single intravenous injection, and found the brain tissue to contain 0.31% of the maximum plasma concentration.

Epidemiological and clinical studies of olive oil phenols Olive oil and its phenolics have received increasing interest because of numerous epidemiological studies. To date, the majority of epidemiological studies involving olive oil is linked to a decreased incidence of many types of cancer,34,35 cardiovascular disease,36,37 and certain types of neurodegenerative diseases such as Alzheimer’s, multiple sclerosis, and aging.38–41 In one human epidemiological study, a high monounsaturated fatty acids intake appeared to be protective against age-related cognitive decline.42 Poorer adherence to the Mediterranean diet is associated with a younger age of Parkinson’s disease onset.20 Meanwhile, high adherence to the Mediterranean

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diet decreases the risk of Alzheimer’s disease and the risk of mortality in these patients.43 Human studies demonstrate that phenolic compounds in olive oil have positive effects on certain physiological parameters, including oxidative damage, inflammatory markers, plasma lipoproteins, platelet and cellular function, antimicrobial activity, and bone health.2 A randomized crossover study has shown that oxidative DNA damage decreased after intake of phenol-rich virgin olive oil.44 Meanwhile, some studies reported that total plasma antioxidant activity increased after the ingestion of olive oil phenolic compounds in human.44,45 A randomized cross over study found that consumption of olive oil significantly lowered markers of oxidative stress such as F2-isoprostane.46 Fitó et al. 47 found that consumption of olive oil phenolic compounds decreased some of inflammatory markers such as interleukin-6. Weinstock-Guttman et al. 21 documented that a low fat diet, diet with olive oil, can have potential to improve the subjective perception of physical and emotional disease burden in multiple sclerosis patients.

Mechanisms of neuroprotective olive oil phenol action Olive oil phenols have a wide array of biological actions. Also, there is accumulating evidence that dietary olive oil and its phenolics have neuroprotective effects both in vitro and in vivo. At present, many of the neuroprotective olive oil phenol’s actions have been identified, but the mechanisms behind these actions have not been fully elucidated. Therefore, further research is needed to identify the molecular pathways and intracellular targets responsible for olive oil phenol’s neuroprotective effects. Their most famous and widely renowned biological action involved in neuroprotection is their free radical scavenging/ antioxidant action, lipid peroxidation inhibition, anti-inflammatory, glutathione restoration, and antiapoptotic properties.

Free radical scavenging/antioxidant actions Free radicals are highly reactive molecules, defined as any chemical compound that has one or more unpaired electrons, which can have damaging effects directly on the cell, particularly on DNA, proteins, and lipids.48 These molecules have been implicated as a potential contributor to the pathogenesis of neurodegenerative diseases.49 Olive oil contains a large amount of antioxidant molecules such as several different phenolic compounds, well-known freeradical scavengers that neutralize the toxic species and sometimes even prevent the early steps of their formation.50–52 In this regard, some studies have shown that olive oil phenolic compounds scavenge a various of endogenous and exogenous free radicals and

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oxidants, including those generated by hypochlorus acid, xanthine/xanthin oxidases, and hydrogen peroxide.12,53 Several mechanisms may account for the antioxidant activity of olive oil phenolics such as chelating of metal ions,54 inhibition of inflammatory enzyme,11 and providing of hydroxyl group for quenching and neutralization of free radicals.12 Meanwhile, total plasma antioxidant activity has also been reported to increase in human after the ingestion of olive oil phenolic compounds.55 In this regard, Bu et al. 15 believe that antioxidative effects of tyrosol are the main mechanism leading to neuroprotection following cerebral ischemia, a dose-dependent neuroprotective effect that peaked at 64.9% in rats treated with physiologic dose of tyrosol (30 mg/ kg). In vitro study has shown that hydroxytyrosol effectively suppressed ortho-phenylphenol-induced reactive oxygen species (ROS) formation.56 A further study demonstrated that tyrosol modulated ROS production.57 Also, it is reported that tyrosol has scaven58,59 ging effects on ONOO− and O− In vitro study has 2. shown that hydroxyl-1-aryl-isochromans, a polyphenolic antioxidant enriched in extravirgin olive oil, effectively abolished hydrogen peroxide.60 Meanwhile, olive phenols prove to be efficient scavengers of hydrophilic peroxyl radicals with a long-lasting antioxidant effect.61 Oleoropein treatment decreases or even prevents Aβ aggregation,62 an extracellular amyloid-β plaque which has a pro-oxidant role and promotes the production of ROS during Alzheimer’s disease. Recent study has shown that extra virgin olive oil (representing 10% of calorie intake in the total standard daily diet of rats) and physiologic dose of hydroxytyrosol (2.5 mg/kg body weight for 14 days) exerted strong antioxidative effects in a 3-nitropropionic acid (3NP)-induced Huntington’s disease-like rat model by reducing lipid peroxidation product levels, blocking glutathione (GSH) depletion, and blocking and reversing the effect of 3NP on succinate dehydrogenase activity.20 A further study demonstrated that the olive oil phenols increase superoxide dismutase activity and decrease tissue levels of 4-hydroxynoneal and 3-nitrotyrosine in an age-related learning/memory impairment model associated with increased amyloid-β protein and brain oxidative damage.26 Jacomelli et al. 63 reported that dietary extra-virgin olive oil significantly increased superoxide dismutase activity (about +60%) and decreased xanthine oxidase (XO) activity (about −25%). Also, an experimental study suggested that olive oil changes brain cytosol antioxidant superoxide dismutases and brain mitochondrial antioxidant superoxide dismutase activity during sexual maturation, thus modulating the susceptibility of nerve cells to free radical oxidative damage.64 Oxidative stress can be indicated by the presence of markers such as F2-isoprostanes, a result of the

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free radical-induced peroxidation of arachidonic acid. In this regard, an animal study has shown that administration of hydroxytyrosol-containing olive oil waste water to rats significantly lowered F2-isoprostane levels.65 Nuclear factor (erythroid-derived-2)-like 2 (Nrf2) is a master regulator of the antioxidant response.66 Diet rich in olive oil phenolics prevents oxidative stress by modulating Nrf2-dependent gene expression.67 Also, hydroxytyrosol positively regulates the antioxidant defense system through the activation of Nrf2 followed by cell proliferation and resistance to vascular injury.68 Lipid peroxidation, an important pathological event in several neurodegenerative diseases, is a complex process involving the interaction of oxygen-derived free radicals with polyunsaturated fatty acids, resulting in a variety of highly reactive electrophilic aldehydes.69 One of the neuroprotective mechanisms of dietary virgin olive oil17,23 and its phenolics such as hydroxytyrosol14 on brain slices damage after hypoxia-reoxygenation, tyrosol15 on transient focal cerebral ischemia, and oleuropein24,25 on spinal cord injury may be due, in part, to its effects on free radical-induced lipid peroxidation. Olive oil reduced tissue lipid peroxidation by 20.3% in brain of hyperlipemic rabbits.70 Also, extra-virgin olive oil and hydroxytyrosol significantly reduced lipid peroxidation product levels in a 3-nitropropionic acid-induced Huntington’s disease-like rat model.20 A component of the antioxidant defense system is enzyme system such as glutathione peroxidase (GSH-px) and glutathione reductase (GR).71 On the other hand, glutathione has been demonstrated to display a potent antioxidant property.72 González-Correa et al. documented that physiologic doses of virgin olive oil (orally for 30 days at 0.25 or 0.5 ml/kg per day) increased glutathione concentration in rat brain slices subjected to hypoxia-reoxygenation.13 Olive oil phenols might have an effect on anxiety-associated behavior, possibly through a modulation of the expression level of glutathione reductase in the cerebral cortex in aging rats, meanwhile, other antioxidant enzymes such as reduced glutathione, oxidized glutathione and glutathione peroxidase were not modulated.18 A study has shown that the reduction in reduced glutathione was significantly smaller in rats given virgin olive oil than in untreated rats.13 Conversely, the increase in the percentage of oxidized glutathione, glutathione peroxidase activity, and the reduction in glutathione transferase after reoxygenation was similar in rats given virgin olive oil and in untreated rat brain slices subjected to hypoxia-reoxygenation.13 Our previous study showed that administration of physiologic dose of oleuropein (20 mg/kg) immediately and 1 hour after spinal cord injury significantly increased the level of GSH compared with those of trauma group.24 Extra virgin olive oil and hydroxytyrosol significantly blocks

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the GSH depletion in a 3-nitropropionic acid-induced Huntington’s disease-like rat model.20 Also extra virgin olive oil increased brain glutathione levels, glutathione reductase activity, and superoxide dismutase activity, and decreased tissue levels of 4-hydroxynoneal and 3-nitrotyrosine suggesting reduced oxidative stress as a possible mechanism for improvement of learning and memory in SAMP8 mice.26

Anti-inflammatory effects Although the most famous and widely renowned properties of olive oil phenolics have long been attributed to the antioxidant and free radical scavenging effects,12 however, emerging evidences have shown the anti-inflammatory effects of these phenolics.73–76 Olive oil phenolic compounds have been shown to exhibit a range of direct or indirect anti-inflammatory activities.74 In this regard, it has been well established that dietary virgin olive oil significantly inhibit inductible nitric oxide synthase (iNOS) activity or the inflammatory mediators that stimulate this enzyme following brain hypoxia-reoxygenation.13 In another study, production of nitric oxide, inhibition of iNOS activity, reduction of lactate dehydrogenase efflux, and reduction of lipid peroxides on brain slices damage after hypoxia-reoxygenation in rats were reported 48.2, 29.1, 51.3, and 37.3% after daily oral administration of virgin olive oil, respectively.17 Also a study documented that oral administration of olive oil ( physiologic doses of 0.5 and 0.75 ml/kg per day) is cerebroprotective in a rat model of ischemia reperfusion by reduction of brain edema, while the lower dose (0.25 ml/kg per day) was without effect.16 Recently, we demonstrated that oleuropein treatment ( physiologic doses of 20 mg/kg immediately and 1 hour after spinal cord injury) significantly attenuated expression of tumor necrosis factor alpha (TNF-α) and IL-1β, the potent pro-inflammatory cytokines, and consequently expression of iNOS and COX-2.77 We also found that oleuropein treatment significantly attenuated expression of poly-(ADP-ribose) polymerase (PARP) and nitrotyrosine,77 and reduced MPO activity,78 which is indicating a reduction of the neutrophil influx in the injured spinal tissue. Another study similarly documented that treatment with oleuropein (1 and 6 h after trauma) aglycone significantly decreased proinflammatory cytokines production such as TNF-α and IL-1β, iNOS expression, neutrophil infiltration, nitrotyrosine, and poly-ADP-ribose (PAR) formation, nuclear factor-kβ expression and IKB-α degradation, protein kinase A (PKA) activity and expression in the secondary injury associated with the mouse model of spinal cord trauma.25 Long-term consumption of olive oil (10% w/w for 11 weeks) have positive effects on neuroinflammation and brain function by modulating brain fatty acid

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composition and the levels of signaling proteins involved in PKA and protein kinase C activation in apolipoprotein E knockout mice brain.79

Anti-apoptotic properties Apoptosis or programmed cell death is a key mechanism of neurodegenerative diseases,80 which is triggered by toxins, radiation, hypoxia, oxidative stress, ischemia-reperfusion, loss of survival/trophic factores, and DNA damage.81 Apoptosis involves active cellular processes leading to a proteolytic digestion of cellular components.82 This digestion is the result of activation of caspases enzymes. B-cell lymphoma 2 (Bcl-2) family proteins have a major role in the mitochondria-dependent pathway of apoptosis, which is involved in activating the caspases.83 Among these proteins, Bcl-2 and Bcl-2-associated X protein (Bax) play antiapoptotic and proapoptotic roles, respectively.84 The ratio of Bax to Bcl-2 determines the cell fate; excess Bcl-2 leads to survival of cells, while Bax induces apoptosis.85,86 In recent years, much attention has been focused on apoptosis because it appears to be susceptible to therapeutic interventions.87 Findings in the model of brain hypoxia-reoxygenation showed that in rats treated with olive oil, brain cell death was 42.5% lower than in untreated rats.13 In explaining this finding, it was documented that olive oil significantly modulates the inducible isoform of nitric oxide synthase in brain tissue.13 A further study showed that pretreatment with virgin olive oil for 30 days and 2 h before middle cerebral artery occlusion ( physiologic doses of 0.5 and 0.75 ml/kg per day) resulted in a reduction of infarct volume, while the lower dose (0.25 ml/kg per day) had no effect.16 Also a study documented that injection of physiologic dose of tyrosol (30 mg/kg) reduced infarct volume on transient focal cerebral ischemia in rats.15 Other studies have shown that lactate dehydrogenase efflux, as a marker of brain cell death, inhibited in a concentration-dependent manner after 7 days of oral treatment with hydroxytyrosol and hydroxytyrosol acetate ( physiologic doses of 5 or 10 mg/kg per day),14 and after virgin olive oil intake12 in rat brain slices subjected to hypoxia-reoxygenation. In vitro study has shown that the olive oil phenolic extract and one of its constituents, gallic acid, exert anti-apoptotic effect against H2O2-induced apoptotic cell death in Hela cells with reduction of time-dependent caspase 9 activity.88 Results of our immunohistochemical assessment showed that the treatment with oleuropein significantly reduced positive staining for Bax, while on the contrary, it significantly increased positive staining for Bcl-2 in the oleuropein treatment groups.24 Conversely, oleuropein inhibited the expression of proapoptotic protein Bax and induced that of the antiapoptotic protein Bcl-2, thereby

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provided the molecular evidence for neuroprotective activity of oleuropein.24 Another study documented that oleuropein aglycone treatment significantly decreased apoptosis (TUNEL staining, FAS ligand expression, caspase 3, Bax and Bcl-2 expression) in an experimental model of spinal cord injury in mice.25

Other mechanisms Further pharmacological activity of olive oil phenolics that may play a role in neuroprotection includes increasing of BBB integrity,16 increasing of neurotrophic factor expression such as glial cell-derived neurotrophic factor,25 hyperpolarization of basal mitochondrial membrane potential as a cytoprotection effect,89 nerve Na (+), K (+)-ATPase activity reduction,23 and decreasing of DNA strand break18 as a marker of oxidative damage.

Conclusion Considerable evidence indicates the Mediterranean diet is linked to a decreased incidence of cardiovascular disease, cancer, and certain neurodegenerative diseases. Olive oil, the main source of fat in the Mediterranean diet, is a good source of phytochemicals including polyphenolic compounds with high bioavailability in humans. Olive oil phenols have proven to be effective in protecting against the general mechanisms of neurodegenerative diseases such as free radical scavenging/antioxidant actions, anti-inflammatory and anti-apoptotic properties in cell culture, and animal models. The evidence presented in this review suggests the potential of olive oil phenolics in both preventive and therapeutic usages for neurodegenerative diseases. Although more studies are required, the biologically relevant properties of olive oil phenolics provide new insights on the mechanisms by which olive oil may contribute to lower incidence of neurodegenerative disorders in the Mediterranean area. Meanwhile, clinical trial researches utilizing olive oil dietary supplementation to assess its potential in prevention and treatment of neurodegenerative disorders remain scarce.

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