PUFAs composed of eicosapentaenoic C and decosahexanoic C acids are particularly vulnerable to free radicals attack due to the double bonds that allow RONS to remove hydrogen ions Hawkins et al. In particular, RONS overproduction in brain cells reacts with cell membrane PUFAs causing their peroxidation Rahman, More specifically, lipid peroxidation generates a heterogeneous group of relatively stable products such as malondialdehyde MDA , 4-hydroxynonenal HNE , acrolein and isoprostane Reed, As a result, membrane fluidity decreases causing a greater permeability.

This facilitates a massive entry of substances into the intracellular system e. Carbohydrates are also influenced by RONS with the formation of advanced glycation products AGE Gabbita et al.

All neurodegenerative disorders share several common characteristics, such as an abnormally aggregated protein accumulation and mitochondrial dysfunction that demonstrate an oxidative stress status Abramov et al. They are able to preclude the protein reduction, cause translation errors in vivo altering protein structure, and function Dukan et al.

In addition, Nitric Oxide NO appears to play an important role in neurological disorders. It has one unpaired electron that makes it highly susceptible to other molecules. Released into the bloodstream, it is oxidized to form nitrite and nitrate Lundberg et al.

The synthesis of NO is regulated by Nitric Oxide Synthase NOS that, in the human body exists in three forms: inducible nitric oxide synthase iNOS , neuronal nitric oxide synthase nNOS and the endothelial nitric oxide synthase eNOS.

The amount of NO, produced by these different isoforms, shows a different physiological activity. At low concentrations, NO seems to have a neuroprotective effect: studies in animals model showed that NOS inhibition correlated with the genesis and the progression of PD, and with a decreased neuronal apoptosis Steinert et al.

Nevertheless, NO at high concentrations, induces a proinflammatory stimulus with a neurotoxic effect Good et al. The risk of developing neurodegenerative disorders is also related to some lifestyle factors, such as obesity, sedentary lifestyle, and unbalanced diet, because of their role in RONS genesis Tan et al.

Therefore, considering the fact that oxidative stress is one of the most important risk factors involved in the onset, maintenance and progression of neurodegenerative diseases, a healthy and balanced diet, with its consequent intake of natural antioxidants, could have a fundamental protective role against them Steele, ; Johri and Beal, ; Kumar and Ratana, ; Khan et al.

The oxidative stress theory and its consequences at cellular level is shown in Figure 1. Figure 1. Model of free-radical formation and its consequences at a cellular level. The intense oxygen consumption in the brain induces the formation of reactive oxygen species ROS.

Their high reactivity leads to an increase of the oxidative stress, which promotes: i glycosylation and oxidation of proteins, leading to the formation of advanced glycation products AGE or loss of protein function; ii DNA damage with oxidation or nitration of guanine bases; iii lipid peroxidation with reduction of membrane fluidity and increase in cell permeability, resulting in alteration of cellular homeostasis.

All these factors can contribute to the development of neurodegenerative disorders. A diet characterized by vegetables and fruits, usually rich in Vitamin C, carotenoids, and Vitamin E, is positively associated with cognitive efficiency and reduced the risk of dementia in the elderly.

From a chemical point of view, Vitamin C is defined as Ascorbic Acid AA. It has six-carbon compound that contain two acid-ionizing groups Ballaz and Rebec, In the human body, the brain is the region with the highest concentration of AA Smythies, This high concentration, attests to the fundamental involvement of AA in the brain function.

Indeed, many studies suggest that AA has a neuroprotective role thanks to an antioxidant activity modulation Harrison et al. This modulation is related to the buffering of the oxidizing species induced by methamphetamine Ito et al. It is interesting to note that the AA activity is quite vast, also considering the interaction with Vitamin E.

Their association is remarkable in the protection of membranes and other hydrophobic compartments Beyer, ; Getoff, A clinical study has highlighted the association between vitamin E and C intake and a delayed AD onset in a group of elderly subjects Shen and Ji, ; similar results were also obtained by Shen and colleagues in Kontush and Shekatolina, In fact, it has been shown that a supplementation of these vitamins and so their greater concentration in cerebrospinal fluids can prevent lipid oxidation in AD patients Taghizadeh et al.

The importance of vitamin C in preventing and combating neurological disorders has also been demonstrated in a recent work: in a murine model, decreased levels of AA levels influenced the neural network development, and this alteration correlated with the pathophysiology of neurological disorders Ikeda et al.

In an in vitro study, Lee et al. Vitamin E is a lipophilic molecule that could be found in plants and in many Mediterranean diet food Schirinzi et al. E is referred to compounds called tocopherols and tocotrienols Ulatowski and Manor, These usually include eight molecules α-, β-, γ-, δ-tocopherols and α-, β-, γ-,δ -tocotrienols , with great antioxidant capacity Jiang, The presence of an electrophilic hydroxyl group on the chroman ring, allows Vitamin E to be a strong antioxidant.

To understand Vitamin E role as a protective factor in neurodegenerative disorders, it must be considered what happens if it is deficient.

For example, it is demonstrated that Vitamin E deficit is related to an impairment of cerebellar Purkinje neurons that are the main integrators of cerebellar neural circuits Ulatowski and Manor, As far as PD, evidence suggests that a Vitamin E supplementation can improve symptoms, functional capabilities and the inflammatory state of affected patients Simonetto et al.

In addition, Khanna et al. Therefore, the use of vitamins E and C as antioxidant supplements is fundamental to delay the onset of neurodegenerative disorders and their complications.

Recently, it has grown an interest in polyunsaturated fatty acids PUFAs and their beneficial effects on health, due to their strong antioxidant properties Fotuhi et al. PUFAs omega-3 and omega- 6 fatty acids usually have two or more double bonds in the carbon chain structure.

Omega-6 fatty acids include linoleic acid LA , γ-linolenic acid GLA and arachidonic acid AA. Omega-3 fatty acids include eicosapentaenoic acid EPA and docosahexaenoic acid DHA. Their intake is important since their limited synthesis in humans Youdim et al. Cell-membrane PUFAs composition could be modified with dietary supplementation but it depends on age and probably also on the quantity PUFAs integration Calder, High fatty acid diet increases their percentage in inflammatory cell membranes of inflammatory cell and reduces AA levels, a stress-related biomarker and an inflammatory process trigger through pro-inflammatory eicosanoids production Calder, ; Dyall, Polyunsaturated fatty acids, in particular EPA and DHA, are interesting because of their beneficial effects in preventing cognitive decline through neuroprotective properties such as increasing nerve membrane neuroplasticity, promoting synaptogenesis, modulating signal transduction pathways in neuronal cells, and attenuating inflammatory processes Youdim et al.

Furthermore, DHA, produced by the desaturation and elongation of α-linolenic acid ALA , is able to influence a certain number of membrane proteins, such as receptors, ion channels and enzymes.

Furthermore, DHA can modulate dopaminergic, serotonergic, and cholinergic neurotransmission, thus regulating signal transduction pathways Parletta et al.

DHA is also considered important for neurogenesis regulation, neural synapses increase and neuronal damage protection Cruz-Jentoft et al. DHA level decreases significantly both in the blood plasma and in the brain, in physiological aging, above all in AD patients Dupont et al.

However, several studies suggest that Omega-3 fatty acid integration is beneficial only in the early stages of cognitive decline Parletta et al. Indeed, there are discrepancies about fatty acid effectiveness on cognitive functioning Jiao et al. A recent double-blind randomized study investigated the effectiveness of fatty acid intake omega-3 and omega-6 combined with other antioxidant vitamins in a group of older people with MCI.

In this study Beaudart et al. An attentional functionality improvement was evidenced too specifically, in a symbol cancelation test and in the Stroop test, in particular in the word and color subtests but not in the test in which the interference inhibition capacity is investigated.

Besides, from a functional point of view, the experimental group obtained high scores in tests investigating muscle strength, endurance, power, and balance. These physical performance parameters are important since they refer to the most demanding daily activities.

In parallel, an increase in the quality of life, sleep and perceived fatigue was demonstrated. The results of this study are similar to what described by Bo et al.

Sinn et al. The same results have not been obtained on patients with known neurodegenerative diseases such as AD, to indicate that greater benefit is drawn from taking PUFA in the early stages of cognitive impairment Chiu et al. Coenzyme Q10 2,3-dimethoxymethyldecaprenyl-1,4-benzoquinone is a fat-soluble compound also known as CoQ10, vitamin Q10, ubidecarenone or ubiquinone.

An endogenous substance is produced by mitochondria in doses of about 3—5 mg per day. It is one of the main elements involved in mitochondrial oxidative phosphorylation and acts as an antioxidant. In vitro studies have shown that CoQ10 easily crosses the blood brain barrier Somayajulu et al.

Thanks to its oxidizing and antioxidant properties, it is a cellular redox state modulator. CoQ10 is located in the internal mitochondrial membrane and protects cells from apoptosis at a morphological and at a molecular level Beal et al. Furthermore, as a lipophilic antioxidant, it can eliminate radicals from membranes, cytosol and plasma.

It plays an important role in PD. In fact, CoQ10 levels are significantly lower than normal in neuron and platelet mitochondria of PD patients. In vitro studies on fibroblasts of PD patients have shown that CoQ10 intake restores the electron transport chain activity.

The first clinical studies on the CoQ10 neuroprotective effects were reported in Beal et al. Muller et al. The antioxidant potential of CoQ10 was further evaluated in a pilot study Chiu et al. Promising results were also observed in a double-blind randomized clinical trial involving patients with remitting-intermittent multiple sclerosis Sanoobar et al.

The experimental group took mg of CoQ10 for 12 weeks, and showed a significant reduction in inflammatory markers, such as tumor necrosis factor α TNF-α , interleukin 6 IL-6 and matrix metalloproteinase 9 MMP Ghasemloo et al.

This interaction resulted fundamental to understand how to counteract neurodegeneration in PD: the study showed that the combination of the microRNA miR and CoQ10 was able to prevent the oxidative damage in dopaminergic neurons and improve motor function induced by 6-Hydroxypopamine injection by reducing matrix metalloproteinase 2,9 in an animal model.

Nigella sativa L. sativa , also known as black cumin, is a plant grown in the Mediterranean countries, in the south and south-west Asia, characterized by its high bioactive-compound content seed e. and its anti-inflammatory, antioxidant, immunomodulating and anticancer properties Gholamnezhad et al.

Its biological activity is associated with its thymoquinone content TQ Bahareh and Hossein, Bordoni et al. Sativa oil grown in the Marche region of Italy and its conservation. Therefore, the Stored Extracted Oil SEO and the Fresh Extracted Oil FEO were obtained from the same cultivation in order to analyze their thymoquinone content.

In murine models, it has been demonstrated that thymoquinone is useful to obtain a delayed onset of the microglia degeneration caused by the oxidative stress Cobourne-Duval et al. In addition, TQ is able to improve and regenerate antioxidants enzymes such as glutathione peroxidase and glutathione reductase previously repressed by Beta-amyloid in differentiated cell lines of rats affected by AD Khan et al.

Moreover, an in vitro study shows that TQ exerts an inhibition on the α-synuclein aggregation reducing the inflammatory state and improving antioxidant bioavailability Ardah et al. Chlorogenic acid CA , the main phenolic coffee component, is another polyphenolic substance with an excellent antioxidant activity.

It belongs to the chlorogenic acid family CGA that are phenolic acids derived from cinnamic acid esterification, such as caffeic, ferulic and p-coumaric acids. The CGA is also widely present in drinks based on herbs, fruits, and vegetables. Chlorogenic acids have antibacterial, antioxidant and anti-inflammatory activities Liang and Kitts, Several in vitro and in vivo studies have highlighted their ability to counteract neurodegenerative events.

Although a preclinical study on AD transgenic mice reported that caffeine reduces brain beta-amyloid Aβ levels Arendash et al. Currently, few studies have analyzed CGA effects on human cognitive impairment. Epidemiological studies have found that coffee drinking habits reduce cognitive impairment and the risk of developing neurodegenerative diseases such as AD Panza et al.

In particular, Kim et al. Eskelinen et al. Recently, Kato et al. Socała et al. Significantly higher scores emerged in tests investigating attentional, executive and mnesic functionality. Previous studies have shown that the CGAs improve blood pressure and vascular endothelial functions, both associated with dementia onset Ota et al.

Saitou et al. Watanabe et al. In this randomized controlled double-blind study, experimental group took a compound based on the CGA caffeoylquinic acids CQA , feruloylquinic acids FQA and dicaffeoylquinic acids diCQA for 16 weeks; CQA—FQA total amount was mg, obtained by extraction from green coffee beans.

Participants underwent a neuropsychological examination MMSE and RBANS at baseline, after 8 weeks and after 16 weeks. At the end of the treatment, significant differences between the CGA intake group and the placebo one was evidenced: in particular, elevated scores were recorded in tests investigating motor speed, psychomotor speed, and executive functions.

The serum concentration of cognitive impairment-linked biomarkers revealed an increase in apolipoprotein A1 ApoA1 and Transthyretin TTR levels in the experimental group at 16 weeks Watanabe et al. Considering these results, the CGA intake may improve not only motor activity, but also the cognitive functions that control its execution and monitor its efficiency.

These results confirm what was described previously by the same authors in a pilot study Eskelinen et al. In PD murine models, the CGA improves motor skills, mitochondrial activity, and the expression of antiapoptotic genes like Bcl-2 while reduces the activation of the proapoptotic ones Saitou et al.

Selenium is an essential micronutrient with a very narrow recommended dietary range. Selenium, in the form of selenocysteine, is a component of 25 selenoprotein classes, including GPx, selenoproteins P, W and R and thioredoxins TrxR. As an antioxidant, it provides protection from ROS-induced cellular damage Brauer and Savaskan, ; Xiong et al.

Considering that older people are more exposed to selenium deficiency due to metabolic changes, lower bioavailability, and diet changes Planas et al. Selenoproteins, such as glutathione peroxidases GPx , play an important role in antioxidant defenses. The main brain selenoproteins are P and GPx: the first one has been identified in senile plaques and neurofibrillary tangles, suggesting its important role against oxidative damage Bellinger et al.

The biosynthesis of selenoproteins depends on selenium availability. Therefore, an adequate selenium intake may be particularly important for maintaining the elderly function Steinbrenner and Sies, Brazil nut Bertholletia excelsa is the richest dietary selenium source, and its intake improves selenium status Thomson et al.

Although some studies have reported that selenium stet is important for maintaining cognitive efficiency Berr et al. Cardoso et al. The experimental group took a 5-gram Brazil nut per day, containing approximately Selenium plasma and erythrocyte concentrations, Gpx activity in erythrocytes, ability to absorb oxygen radicals and MDA, and lipid peroxidation genotoxic product were recorded at baseline and after 6 months.

The CERAD neuropsychological battery assessed cognitive functions. Furthermore, an increase in plasma and erythrocyte selenium concentrations was observed in the experimental group, there was also a significant improvement in erythrocyte GPX activity.

Although no intergroup changes emerged in overall cognitive performance, assessed with the CERAD total score, subtests investigating constructive praxis and verbal fluency showed higher scores in the treated group.

Probiotics refer to a group of live nonpathogenic microorganisms, which, when administered in adequate amounts, can establish the microbial balance, particularly in the gastrointestinal tract Wang et al.

Their importance is also related to their antioxidant properties: they act as metal-ion chelators, have their own antioxidant enzymatic systems SOD and CAT , can produce various metabolites GSH, butyrate and folate and mediate Antioxidant Signaling Pathways Wang et al.

Bagga et al. Therefore, a rational manipulation of intestinal microbiota through probiotics, could affect positively Central Nervous System-associated disorders. Bonfili et al. A clinical trial by Kobayashi et al.

breve A1 on behavior and physiological processes in AD model mice. The consumption of B. breve A1 suppressed the hippocampal expressions of inflammation and immune-reactive genes that are induced by amyloid-β suggesting that B.

breve A1 has therapeutic potential for preventing cognitive impairment in AD. Michael et al. Both consortia were equally able to attenuate intracellular reactive oxygen species accumulation in SH-SY5Y cells. Another clinical trial showed that heat-killed L. buchneri KU has an important antioxidant activity mediated by its ability to increase levels of BDNF and so its intake can be considered useful in PD prevention Cheon et al.

Therefore, in accordance with the above, thanks to their antioxidant properties, probiotics seems to be fundamental to delay the progression of these neurodegenerative disorders Figure 2. Figure 2. Antioxidants with neuroprotective properties.

Following the detachment of Keap1 subunit, Omega-3 increases the antioxidant genes expression. Vitamins E, C, and Nigella sativa rich in vitamins neutralize free radicals thanks to the presence of an electrophilic hydroxyl group on the chromane ring.

Coenzyme Q10 CoQ10 plays a fundamental role in the electron transport chain protecting cells from apoptosis at a morphological and molecular level. Selenium is able to reduce neurofibrillary tangle formation while chlorogenic acid reduces amyloid deposition.

Probiotics act as metal ion chelators and as antioxidants using their antioxidant enzyme systems: superoxide dismutase and catalase SOD and CAT. Lots of natural compounds contain antioxidant molecules that are protective against free radical damage affecting brain cells. In vitro and murine models have widely demonstrated that antioxidant improve oxidative stress status of brain cells, cognitive functions and motor skills.

Further clinical trials should be conducted in order to understand if these natural compounds, alone or in combination with an appropriate pharmacological treatment, can effectively delay the potential onset of neurodegenerative disorders and ameliorate brain functions. Moreover, it should be better elucidated the actual bioavailability in the central nervous system of these natural antioxidants, and their effective ability to pass the blood brain barrier after an oral intake.

MA and JF: formal analysis of scientific literature. FF, GS, and SG: writing—original draft preparation. FF and GS: writing—review and editing. CP: supervision. All authors have read and agreed to the published version of the manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers.

Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. Abramov, A. Interaction of misfolded proteins and mitochondria in neurodegenerative disorders. doi: PubMed Abstract CrossRef Full Text Google Scholar. Ahmed, N.

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Sarcopenia: revised european consensus on definition and diagnosis. Briefly, the results of this study are not enough to evaluate the effect of vitamin A on the cognitive performance of MS patients.

More studies with larger and non-heterogeneous sample sizes are required. Boswellia papyrifera is an Iranian traditional herb from the trees of the genus Boswellia Anti-inflammatory and anti-arthritis effects of Boswellia extract have been supported by clinical studies Moreover, it has been shown that Boswellia could improve the formation of new neuronal networks as in neurodegenerative diseases such as MS these networks are destructed which leads to cognitive impairment We identified only one study that reported the effect of Boswellia papyrifera on cognitive domains This study showed that this antioxidant could improve visuospatial memory, but not information processing speed and verbal memory.

No significant effect of Boswellia on verbal memory could be due to its dose-dependent effect as was shown in two studies conducted by Mahmoudi et al.

Therefore, to identify the exact effect of Boswellia on cognitive domains of MS patients, studies with different Boswellia papyrifera dosages are required. Moreover, the effect of Boswellia papyrifera on the cognitive performance of MS subjects could be influenced by sex as men in this study did not improve in the SDMT test.

Studies have shown that omega-3 has immunomodulatory and anti-inflammatory properties, making it clinically beneficial to reduce inflammation and improve cognition in MS patients.

Moreover, it has been reported that omega-3 could increase the activity of glutathione peroxidase GH , one of the most important endogenous antioxidants, leading to reduced inflammation and cytokine release A study conducted by Jelinek et al.

reported that omega-3 supplementation reduces perceived cognitive impairment in MS patients It is recommended to use an antioxidant-containing regimen diet accompanied by the administration of a healthy diet and lifestyle in these patients.

This was well shown in Lee et al. In this study patients with MS were prescribed the home-base intervention consisting of 1 a modified Paleolithic diet; 2 exercise; 3 neuromuscular electrical stimulation; 4 stress management.

According to the results of this study, the combination of a healthy lifestyle and diet could improve mood and cognition in MS patients To report the limitations of this study, we did not include case reports and non-English studies. Each study measured cognitive domains using different cognition scales with different sensitivity to track cognitive function in MS patients.

Furthermore, some of the included studies did not use an antioxidant as monotherapy but rather used a multimodal such as a Mediterranean diet that is consisted of other neuroprotective factors and non-pharmacological interventions.

Therefore, we cannot conclude that cognition improvement was solely dependent on the antioxidant itself. It is complicated to draw a conclusion regarding the effect of antioxidant containing regimen and cognitive performance in MS patients.

Findings from included studies failed to unequivocally support the beneficial effect of antioxidant consumption on cognitive performance in MS patients.

This could be due to limited available studies on each nutrient, short duration of follow-up in some studies, and small sample size.

In addition, subjects of several studies were heterogeneous, meaning that there were patients with different duration of disease onset. Furthermore, the sensitivity of each cognition test is different and may require a longer duration to detect cognitive performance in MS patients.

We do not have any financial support for this study. Conflict of interest. The author declares no conflict of interest regarding the publication of this paper. Ethical approval. Not applicable. Availability of data and material. The datasets analyzed during the current study are available upon request with no restriction.

Consent for publication. This manuscript has been approved for publication by all authors. Nabizadeh, F. Antioxidant supplements and cognition in Multiple Sclerosis: a systematic review. Neurology Letters , 1 2 , doi: Fardin Nabizadeh; Fatemeh Sodeifian; Ali Ghaderi; Amir Mohammad Sharafi; Mohammad Balabandian.

Neurology Letters , 1, 2, , Neurology Letters , ; 1 2 : Login Register. Neurology Letters. Advanced Search. Full Text Introduction Multiple sclerosis MS is an immune-mediated, and neurodegenerative disease of the central nervous system CNS , characterized by demyelination, inflammation, and blood-brain barrier breakdown 1, 2.

Methods and Materials This study was performed based on the Preferred Reporting Items for Systematic Review and Meta-Analysis PRISMA Search strategy We searched PubMed, Embase, Scopus, and Web of Science for the identification of relevant studies in November Eligibility criteria We included control trials, cohort, case-control, and cross-sectional studies which showed the effect of any type of antioxidants on cognitive performance in MS patients.

Study selection Two investigators A. Data extraction The same reviewers A. Quality assessments Publication bias of entered studies was performed using the Cochrane Risk of Bias Tool Data synthesis and analysis The extracted data were qualitatively compared and quantitative data represent as a percentage, mean, and range.

Results Study selection Our initial search yielded papers. Characteristics of included studies and quality assessments We identified eight randomized clinical trials RCT , two cohorts 28, 29 , and two open trials 30, 31 studies with a total of subjects.

Main findings Our review included three studies that examined the effect of ginkgo Biloba 20, 27, 30 on cognitive performance, two examined Mediterranean dietary 24, 26 , and remained studies one each investigated the vitamin A 28 , Omega 5 21 , Omega 3 29 , estriol 22 , epigallocatechingallate EGCG 23 , Boswellia papyrifera 25 , and paleolithic diet Deceleration Funding We do not have any financial support for this study.

Conflict of interest The author declares no conflict of interest regarding the publication of this paper. Ethical approval Not applicable Availability of data and material The datasets analyzed during the current study are available upon request with no restriction.

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