Plants Oil and Multiple Sclerosis

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1		Ghanya Al-Naqeb	--	4413	2023-11-21 10:35:43	\|
2	format	Jason Zhu	-5 word(s)	4408	2023-11-22 02:27:01	\|

This entry is adapted from the peer-reviewed paper 10.3390/nu15224827

Multiple sclerosis disease (MS) is a 38.5 chronic neurological autoimmune disease that affects the nervous system, and its incidence is increasing globally. There is no cure for this disease, and with its severity and disabling variety, it is important to search for possibilities that could help to slow its progression. It is recognized that the mechanisms of MS pathology, its development and degree of activity can be affected by dietary factors.

multiple sclerosis plant oils polyunsaturated fatty acids EAE model

1. Pomegranate Seed Oil

Pomegranate seed oil (PSO) is obtained from pomegranate (Punica granatum) seeds, with a content of around 12% and 20% of the total seed weight ^[1]. Pomegranate seed oil is rich in PUFAs, among which the conjugated linolenic acid content is up to 80% of the total PUFAs with a varied isomeric distribution ^[2]. Among these isomeric distributions, punicic acid was identified as the active compound in PSO ^[3]. Pomegranate seed oil also contains linoleic acid (13–20%), oleic acid (8–9%), linolenic acid (0.06–0.08%) and arachidic acid (0.68–0.90%) as well as important fatty acids such as gallic acid and ellagic acid ^[4]. Other important bioactive compounds including phenolic compounds, tocopherols and phytosterols are also present in PSO ^[5].

Pomegranate seed oil has been reported to have a protective effect against oxidative stress, increasing antioxidant activity and reducing inflammation biomarkers ^[6]. In addition, PSO was shown to reduce plasma interleukin-6 and tumors necrosis factor levels in high-fat-diet-induced obese mice ^[7]. Furthermore, PSO nanoemulsion prevented a cognitive and behavioral decline in mice induced with traumatic brain injury, reduced neuronal death and also prevented mitochondrial damage ^[8]. Interestingly, many biological effects including antioxidant, anti-inflammatory, anti-cancer and anti-apoptotic of PSO were related to the presence of a high amount of punicic acid and punicalagins ^[9].

Regarding MS, PSO was reported to improve cognitive dysfunction in MS patients. In this regard, in a single-center, randomized double-blind placebo-controlled clinical trial, Petrou et al. ^[10] investigated the effect of a 3-month treatment of nanoemulsion formulation of PSO, named GranaGard, on 30 MS patients in combination with their immunomodulatory MS-treatments. Two cognitive tests that are known to be sensitive in the detection of cognitive dysfunction—namely, the Expanded Disability Status Scale (EDSS) ^[11] and Multiple Sclerosis Functional Composite ^[12]—as well as cognitive tests including the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) ^[13], were applied. The outcomes indicated a cognitive improvement in MS patients treated with PSO nanoemulsion in all of the tested measures, with no adverse effect when compared to untreated patients. The possible effect of PSO nanoemulsion on the improvement of cognitive dysfunction in MS patients was suggested to be due to the antioxidative effects of PSO nanoemulsion and its main active ingredient, punicic acid. Punicic acid is known to achieve neurodegenerative prevention through different mechanisms ^[14] by reducing Reactive Oxygen Species (ROS) generation and lipids peroxidation in both in vitro models and in humans ^[15]^[16].

Again, in the EAE animal model experiment by Binyamin et al. ^[17], the administration of PSO in two different forms—as 10% oil/water nanoemulsion either through oral gavage or mixed with diet at 25 or 75 mL of PSO/kg of the diet—were conducted for 10 days. EAE female mice treated with PSO supplemented with diet showed a reduction in disease symptoms and burden. This effect was even greater when the PSO was administered as the nanoemulsion formulation. The administration of PSO in nanoemulsion form showed a dramatic reduction in demyelination and oxidation of lipids in the brains of the treated mice compared to the untreated mice.

Additionally, it was clear that, while the administration of large doses of PSO with diet can reduce MS disease burden in EAE mice, PSO nanoemulsion exerted a wider effect at a much lower dose. Pomegranate seed oil nanoemulsion increased the bioavailability, and the activity of PSO as nanoemulsion has been reported to be an effective delivery system ^[18]. In addition, EAE mice treated with PSO nanoemulsion showed a reduction in malondialdehyde (MDA) levels, a product of lipid peroxidation, which was shown to be increased in the blood and serum of patients with MS ^[19]. Recent evidence indicates that oxidized lipids are neurotoxic and have pro-inflammatory properties, and lipid peroxidation products could be involved in demyelination and axonal injury in MS ^[20]^[21].

Pomegranate seed oil was also found to have a neuroprotective effect on transgenic mice mimicking a genetic prion disease ^[22], where nanoemulsion of PSO successfully inhibited the disease onset in treated mice compared to untreated mice. Lipid oxidation and neuronal loss were decreased in the treated mice, indicating that the PSO nanoemulsion had a strong neuroprotective effect. Pomegranate peel extract has been shown to have a beneficial effect against MS disease in EAE mice, where it was reported that the pomegranate peel extract resulted in a decrease in clinical symptoms, demyelination and axonal damage in EAE mice ^[23].

2. Sesame Oil

Sesame oil (SSO) is obtained from the seed of sesame (Sesamum indicum L.), with a content of 37–63% of oil. It is rich in PUFAs and counts for 82%, along with a balanced amount of linoleic and oleic acid ^[24]. Sesame seed oil is known for its nutritive and health promotion values; indeed, SSO consumption has been shown to reduce blood glucose levels and to have beneficial effects on lipid peroxidation and antioxidant levels in streptozotocin-induced diabetic rats ^[25]. In addition, SSO was reported to have anti-inflammatory effects through the reduction in proinflammatory cytokines, as well as antioxidative effects ^[26].

Regarding MS, it was reported that the combination therapy of interferon beta-1a with SSO induced immune modulation by increasing regulatory cytokines ^[27]. In a randomized controlled trial with 93 patients with MS, the control group (n = 39) received 30 μg/week of interferon beta-1a intramuscularly and the treated group with SSO (n = 54) received interferon beta-1a—that is, the same as the control group, with the addition of 0.5 mL/kg/day of oral sesame oil—for 6 months. As a result, interleukin (IL) 10 concentration, leukocyte proliferation and nitric oxide (iNOS), as well as inflammatory cytokines including IFN-γ and TNF-α, were significantly reduced in the patients treated with SSO compared to the patients treated with interferon beta-1a alone. The reduction in inflammatory cytokines and nitric oxide was suggested to be attributed to the presence of anti-inflammatory agents in SSO that could show anti-inflammatory effects ^[27]. Sesame oil was reported to contain different lignans, including sesaminol, sesamolin, pinoresinol and sesamin, and these lignans are the compounds responsible for the antioxidant and anti-inflammatory properties ^[28].

It was recognized that there is a relation between the severity of MS disease and the number of IFN-γ. IFN-γ is an important cytokine of cell-mediated immunity, which is mainly produced by macrophages and T cells ^[29]. IFN-γ has been reported to increase MS severity through leukocyte infiltration in the brain, the activation of macrophages and iNOS production ^[30]. Previous studies have indicated that during MS and EAE conditions, there is an enhancement in IFN-γ levels ^[31]. In addition, it was found that anti-IFN-γ has a positive impact on TH1-mediated autoimmune disorders ^[32]. In this regard, the cytokine modulatory effects of SSO on EAE female mice were reported by Javan et al. ^[33]; mice were injected intraperitoneally every day with SSO at 4 mL/kg/day for 20 days and control mice were injected intraperitoneally with 4 mL phosphate buffer. As a result, SSO was able to significantly reduce the disease severity in comparison with the control mice. Sesame oil induced TH2- and TH17-related immune responses and suppressed the TH1 type in EAE. In regard to the IFN-γ levels, IFN-γ were reduced significantly in the treated mice and the level of IL-10 production was increased in the EAE mice treated with SSO compared to the untreated mice. It was reported that IL-10 has a suppressive effect on EAE progression by acting through the modulation of TH1 responses and reducing IFN-γ production, which leads to a decrease in the disease severity ^[34].

3. Acer Truncatum Bunge Seed Oil

Acer truncatum bunge oil (ATBO) is an edible oil obtained from the seeds of Acer truncatum bunge. The oil was characterized to be rich in PUFAs, which counts for about 92%, including ω-9, ω-6 and nervonic acid ^[35]. Nervonic acid deficiency has been associated with neurodegeneration, and supplementation with nervonic acid nutraceuticals has shown an improvement in brain development and cognition ^[36]. Several health benefits of ATBO have been reported; for instance, ATBO inhibited the differentiation of 3T3-L1 adipocytes cells by inhibiting fatty acids synthesis and reducing the number and the size of the cells, suggesting that ATBO might be used in obesity treatment ^[37]. In addition, ATBO had the ability to improve the learning and memory of aging mice by downregulating the inflammation factor at the gene expression level ^[38]. Moreover, there was an improvement in cognitive function in the memory of rats treated with ATBO because of essential fatty acids, including nervonic acid ^[35].

Multiple sclerosis has been known to cause abnormalities and neuroinflammation in the brain. Cuprizone-induced mice have been used as an animal model of demyelination and remyelination and for the examination of the neuroinflammation and oligodendrocyte dysfunction hypotheses ^[39]. Thus, the beneficial effect of ATBO administration on the remyelination process in a mouse model of MS induced with Cuprizone was investigated ^[40]. Cuprizone-induced mice were treated with a diet supplemented with 4% of ATBO for 6 weeks.

4. Hemp Seed Oil and Evening Primrose Oil

Hemp seed oil (HSO) is known as a functional food ^[41]. It is rich in essential fatty acids, with a PUFAs content of over 80% ^[42]. The PUFAs most prominently presented in HSO are linoleic and α-linolenic acids, with a content of 50–70% and 15–25% of total oil, respectively ^[43]. The ω6/ω3-PUFA ratio in HSO is reported to be between 2:1 and 3:1, which is considered optimal for human health ^[44]. In addition, HSO contains alpha-linolenic acid (GLA) and stearidonic acid, which act as biological precursors for longer-chain ω-3 fatty acids ^[40]. A significant quantity of important antioxidants, including carotenoids, tocochromanols, chlorophyll, terpenes, phytosterols, tocopherols and polyphenols, has been reported in HSO ^[45]. Hemp seed oil has been used to treat various disorders for many years in traditional medicine. Several researchers have studied the health-benefit effects of HSO, including antioxidant and anti-inflammatory activities ^[46]^[47]. Evening primrose oil (EPO) is obtained from the evening primrose seed plant, with the scientific name of Oenothera biennis, which belongs to the family of panacea plants. Evening primrose oil is rich in linoleic acid and contains oleic acid and γ-linolenic acid (8–14%) ^[48].

MS is a chronic inflammatory and neurodegenerative disease of the brain and spinal cord, which leads to disability and functional loss due to demyelination and neuronal injury ^[49]. In MS, PUFAs exert immunosuppressive actions through their incorporation into the immune responses and affect cell function within the central nervous system ^[50]. Antioxidants can support cellular defenses in various ways, including radical scavenging, interfering with gene transcription, mRNA ex-pression, enzyme activity and chelation. Both dietary antioxidants and PUFAs have the potential to reduce MS disease symptoms by targeting specific mechanisms and supporting recovery in MS ^[51]. In this line, a study was reported by Rezapour-Firouzi et al. ^[52] that used the EAE MS animal model. Female mice were treated with a combination of EPO/HSO for 2 weeks at 50 λ/mouse orally. The percentage of essential fatty acids, including linoleic, gamma-linolenic acid, dihomo-γ-linolenic acid and arachidonic acid, and ratios of polyunsaturated fatty acids (ω3/ω6-PUFAs) significantly elevated the cell membrane of the spleen and blood of linoleic, gamma-linolenic acid, dihomo-γ-linolenic acid and arachidonic acid in blood samples of treated animals in comparison with untreated animals. In addition, the relative expression levels of IL-4, IL-5 and IL-13 genes in the lymphocytes and serum levels of IL-4 were significantly increased in the HSO/EPO-treated animals compared to the untreated animals. Moreover, the histological assessment showed no demyelination in the brain and spinal cord sections of the EPO/HSO-treated mice in comparison to the non-treated mice. The positive effect of the combination of both oils for remyelination for the treatment of EAE is suggested to be because of the antioxidants and PUFAs presented in both oils ^[52]. Of importance, arachidonic acid is a precursor of pro-inflammatory prostaglandin (PG)E2, but docosahexaenoic acid and di-homo-γ-linolenic acid are precursors of the anti-inflammatory PGE3 and PGE1 series ^[53]. Because of the effective anti-inflammatory activity of GLA, EPO is regularly recommended for the treatment of inflammatory and autoimmune disorders. The earliest results of the use of EPO and colchicine combined therapy in MS patients suggested that it may be of considerable value ^[54].

In the immune system, it was identified that the T regulatory cells act as suppressors of T cells, which are a subset of T cells that modulate the immune system, maintain tolerance and prevent autoimmune disease. In the EAE MS model, interleukin 10, derived from T regulatory cells and T helper, is known as an anti-inflammatory cytokine that can prevent and/or reverse EAE symptoms ^[55]. A previous study showed the effectiveness of rapamycin (RA-PA) as an inhibitor of mTOR signaling in the development of tolerance through the expansion of T regulatory (Treg) cells ^[56]. In this line, the immunomodulation and remyelination activities of a combination of HSO/EPO supplements on the EAE MS model in comparison with RAPA were investigated ^[55].

Additionally, EPO was found to reduce overall life satisfaction in patients with MS. Majdinasab et al. ^[57] conducted a double-blind randomized clinical trial of 52 MS patients and categorized them into two groups, receiving 1 g oral capsule containing EPO every 12 h for 3 months of EPO or placebo, in addition to the standard treatment for their disease.

As the liver is the main organ for drug detoxification and digestion, it was shown that the liver enzyme levels were elevated due to the treatment of MS-like Interferon-β (IFN-β) ^[58]. Interferon-β was shown to shift the immune response from the Th1 to Th2 pattern by enhancing the anti-inflammatory Th2 cytokines and decreasing the production of pro-inflammatory Th1 cytokines. A double-blind randomized trial with MS patients was conducted to investigate the effect of the combination of EPO/HSO on the liver enzymes activity, including alanine transaminase (ALT), aspartate-aminotransferase (AST) and gamma-glutamyl transferase (GGT) ^[59]. The treated patients received a combination of HSO and EPO with a 9/1 ratio at 18–21 g/day (6–7 g, three times daily) and the control patients received the same dose of olive oil. The study indicated that diets supplemented with virgin EPO/HSO for 6 months resulted in a reduction in enzyme activation compared to untreated MS patients, a reduction in clinical symptoms of MS and the patients’ general health improved. The possible mechanism suggested for this effect is due to the antioxidant compounds that are presented in both oils, which were responsible for improving the activity of liver enzyme ^[59].

5. Coconut Oil

Coconut oil (CO) is obtained from coconut trees (Cocos nucifera), with a content of 65–75% of oil, and it has been used widely in food and industries ^[60]. Although CO may have some adverse effects because of its saturated fatty acid content ^[61], several biological activities of CO have been reported, including anti-oxidative and anti-inflammatory ^[62], as well as its ability to improve Alzheimer’s disease ^[63]. Extra virgin coconut oil (EVCO) has been suggested to be a nutritional alternative for patients with MS disease due to the ketone bodies obtained from EVCO, in addition to its numerous benefits linked to MS pathogenic mechanisms, including neuroprotective and anti-inflammatory effects ^[64]. Coconut oil was also reported to be a neuroprotective agent, showing a favorable effect on stroke incidence and survivability through histopathologic analysis of the brain using a stroke-prone spontaneously hypertensive rat model ^[65].

A recent human study showed that patients with MS were examined for a diet intervention enriched with EVCO for 4 months and supplemented with epigallocatechin gallate at 800 mg. The treated patients received 60 mL of extra EVCO divided into two equal intakes (30 mL in capsules for breakfast and 30 mL for lunch), and the control placebo received capsules containing microcrystalline cellulose, the same size and color, with EVCO for 4 months. The administration of EGCG and EVCO showed a neuroprotective effect, where a significant improvement in gait speed, quantitively balance and muscle strength were observed in the treated patients compared to the control patients, and this effect was due to the ketone bodies that may be formed from EVCO metabolism balance. This effect was suggested to be related to muscular improvements, which have been evidenced through the increase in ketone bodies in the blood ^[66].

Based on the literature, VCO contains saturated medium fatty acid that is readily absorbed in the gut ^[67], and the biotransformation of VCO into acetoacetate in the liver can be further metabolized into β-hydroxybutyrate (BHB) ^[68]. BHB is a by-product of lipid metabolism, which is known as a ketone body that has been reported to stand out for its neuroprotective effect observed after stroke and neurodegenerative diseases, as well as its anti-inflammatory effects ^[69]. Ketogenic diets have demonstrated neuroprotective, anti-inflammatory properties that may be effective for nondegenerative disorders including MS. Ketogenic diets have been shown to reduce ROS generation, upregulate antioxidant pathways, activate neuroprotective macrophages and suppress proinflammatory cytokine production ^[70]^[71]. Furthermore, the intervention of MS patients with a combination of EVCO with epigallocatechin gallate for 4 months has resulted in a significant decrease in the serum concentration of IL-6 and patients’ anxiety and an improvement in the functional capacity of the treated patients ^[72].

6. Walnut Oil

Walnut oil (WO) is obtained from walnut kernels (Juglans regia Linne) with a content of about 52–70% of oil, and it is a rich source of PUFA, accounting for 69–73%. Linolic acid is the major fatty acid, counting for 56%, and linolenic acid counts for 12%, while MUFAs account for 17.8–21.2% ^[73]. Walnut oil was noted to contain a considerable number of phenolic compounds. The main phenolic compound is tocopherol, and γ-tocopherol accounted for 80% of the total tocopherol. Walnut oil is also rich in phytosterols. B-sitosterol is the highest, accounting for 80% of the total phytosterol content ^[73]. Overall, WO has been reported to exert several health-benefitting activities, including cognitive impairment and memory deficits ^[74]. Moreover, WO has been shown to inhibit oxidative stress in the brain and prevent scopolamine-induced histological changes in hippocampal CA1 and CA3 neurons ^[75].

An experiment of the effect of WO on EAE animal model of MS was conducted by Ganji et al. ^[76]. Specifically, feeding mice a daily dose of 5 mL/kg of WO for 21 days showed a reduction in the severity of MS mice disorder and significantly decreased the serious sickness in the treated mice by reducing T-helper1 activity. Also, WO caused an improvement in the immune response, where it shifted from destructive to regulatory, suggesting that WO can be used in MS therapy. Walnut oil treatment enhances the T-helper 2 call response. It appeared that the reaction of T-helper 1 can be restrained by T-helper 2 cells through cytokine generation containing IL−4, IL-5, IL-10 and tumor growth factor-β. In mice treated with WO, there was a reduction in disorder severity and a modification in cytokine compared to mice not treated with WO. The possible mechanisms through which WO exerted its effect on reducing the seriousness of MS illness in EAE-treated mice were suggested to include anti-inflammatory mechanisms through the suppression of inflammatory cytokine production, the modulation of cytokine signal transduction pathways and the inhibition of adhesion molecule expression ^[76].

7. Essential Oil from Pterodon emarginatus Seeds

Essential oil from Pterodon emarginatus seeds (EOPS) is obtained from the seed of Pterodon emarginatus, which belongs to the Leguminosae family, and originates from Brazil. The chemical characterization of EOPS shows that the oil is composed of volatile aromatic terpenes including caryophyllene, β-elemene, germacrene-D, α-humulene, spathulenol and bicyclogermacrene ^[77]. Previous research reported that some of the natural triterpenes could modulate some of the immune response markers of EAE MS animal model experiments ^[78]. Essential oil from Pterodon emarginatus seeds had a positive effect in decreasing the development of autoimmune diseases by impairing both the B and T cell responses involved in disease development. The immunomodulatory effect of EOPS on collagen-induced arthritis animals has also been reported ^[79]. As a result, EOPS reduced the severity of arthritis and decreased the serum anti-CII IgG antibody and CD4 + CD69 + lymph node cell number compared to untreated animals.

Microglia is the bone marrow derived from resident macrophages of the central nervous system (CNS). Studies have used a localized activation of microglia as an in vitro model to study the pathogenesis of several neurodegenerative disorders, including Parkinson’s disease, Alzheimer’s disease and MS ^[80]. Alberti et al. ^[81] investigated the effects of EOPS on the progression of MS in vivo using an EAE model experiment and in vitro using microglia. EAE mice received oral treatment of E0PS at 50–100 mg/kg, while control animals were administrated with an oral Vehicle solution. The oral administration of EOPS at 100 mg/kg significantly reduced the neurological signs and development of MS in the EAE experiment compared to the untreated animals. The Th1 cell-mediated immune response was inhibited and the Treg response was upregulated by EOPS in the treated mice and microglial compared to the untreated animals and microglial cells. In addition, EOPS was able to inhibit the microglial activation and expression of iNOS synthase, associated with the inhibition of axonal demyelination and neuronal death, during the development of the disease. The inhibition of CD4+T lymphocytes, inhibition of microglial activation and reduction of the expression of pro-inflammatory mediators were the suggested mechanisms through which EOPS exerts its immunomodulatory effect in vivo and in vitro ^[81].

8. Flaxseed Oil

Flaxseed oil (FSO) is obtained from flaxseed (Linum usitatissimum L.), which is among the richest sources of α-linolenic, which counts for about 58%, followed by linoleic acid with 16% and oleic acid with 21% ^[82]. Flaxseed oil seems to have several health benefits, including anti-inflammatory ^[83] and antioxidant activities ^[84]. In addition, FSO was reported to improve cognitive function in healthy older adults and to improve verbal fluency performance ^[85]. Moreover, it was found that pretreatment with FSO exhibited neuroprotective effects on neurons of the motor cortex area and enhanced the functional motor recovery following cerebral I/R injury by increasing the brain-derived neurotrophic factor and glial cell-derived neurotrophic factor levels ^[86].

Regarding the effect of FSO on MS, only one study was found in the literature ^[87]. Jelinek et al. ^[87] conducted a study on a large cohort of MS patients. The information provided referred to the type of MS, disability health-related quality of life, relapse rates and frequency of fish consumption and ω-3 supplementations, mainly as flaxseed oil. Interestingly, a reduction in the relapse rate was seen at a large level (over 52%) for those MS patients who took flaxseed oil in univariate analysis. Also, FSO-supplemented MS patients were the strongest group, resulting in a significant reduction in disability. The authors claimed that FSO showed a stronger association with quality of life, disease activity and disability than fish oil. The possible mechanism of the FSO effect on MS might be due to its anti-inflammatory and antioxidant action ^[87]. As was shown, FSO supplementation into the diet of diabetic rats resulted in the enhanced activity and upregulation of the mRNA level of hepatic antioxidant enzymes and down-regulated the expression of hepatic inflammatory genes including TNF-α, IL-6, MCP-1, INF-γ and NF-κB. Therefore, the FSO diet prevented tissue injury and alleviated diabetes in diabetic rats ^[83].

9. Olive Oil

Olive oil is rich in MUFAs in the form of oleic acid, with a content of 55–83%, but also α-linolenic acid (3–19%), phenolic compounds, sterols, tocopherols, polar pigments (pheophytins and chlorophylls), triterpenic, dialcohols and hydrocarbons, including squalene and the carotene β-carotene and xanthophylls ^[88]. Olive oil was reported to inhibit food-borne pathogens and stimulate useful microorganisms like L. acidophilus and B. bifidum, which are known as probiotic strains, with potential health benefits after consumption. In addition, a diet rich in virgin olive oil (VOO) could modulate the gut microbiota in both animals and humans ^[89]^[90]. Studies have shown that olive oil has an anti-inflammatory effect in vivo and in vitro ^[91]. In addition, olive oil was reported to modulate the activation of pro-inflammatory genes and reduce inflammatory cytokine expression ^[92]. Moreover, there is accumulating evidence that the regular consumption of the Mediterranean diet, which contains VOO as a main ingredient, is associated with a reduction in developing chronic diseases such as cardiovascular diseases ^[93].

According to the literature, the natural antioxidants present in olive oil, including phenolic compounds and vitamin E, reduce neuron damage by inhibiting the generation of ROS, apoptosis, protein oxidation and damage to the cell membrane and by decreasing βamyloid toxicity ^[94]. Oleacein is a phenolic compound from extra virgin olive oil (EVOO), it is one of the main secoiridoids of the EVOO minor compounds that many health benefits of EVOO have been attributed to ^[95]. Furthermore, oleocanthal may have the ability to counter inflammation in the brain by decreasing the acting astrocytes activation and proinflammatory cytokines level ^[96]. Gutiérrez-Miranda et al. ^[97] examined the potential protective effect of olive oil secoiridoid oleacein on intestinal barrier dysfunction using the EAE female MS model. Olive oil was dissolved in normal saline containing 5% DMSO and mice were injected intraperitoneally with 10 mg/kg/day, while control mice were injected with a vehicle control solution of DMSO/saline for 24 days. Olive oil oleacein showed protection against EAE-induced superoxide an-ion and the accumulation of protein and lipid oxidation products in the colon. In addition, oleacein could enhance antioxidant activity. These effects reduced the colonic IL-1β and TNFα levels in the treated EAE mice. Olive oil leacein could effectively regulate intestinal oxidative stress, inflammation and permeability when administered to EAE mice. It was reported that the polyphenols present in EVOO reduced morbidity and slowed down the progression of neurodegenerative diseases ^[98]. In addition, EVOO polyphenols were also found to reduce inflammation and oxidative stress and modulate the immune system by affecting white blood cell activity and cytokine production ^[99]. According to Carito et al. ^[100], polyphenols of olive oil may have a role in the regulation of neurotrophic levels—and in particular, nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF)—in animal models and humans, and this effect was suggested through the potentiation of neurotrophins’ action ^[100].

Patients with MS can show cognitive and mental health impairment, which has been recognized as an important factor that affects the quality of life of MS patients ^[101]. Chatzikostopoulos et al. ^[102] studied the effects of early-harvest extra virgin olive oil (EH EVOO) on the cognition and mental health of primary or secondary progressive multiple sclerosis human patients. The multiple sclerosis patients were asked to consume three tablespoons of EH EVOO per day for one year. As a result, the consumption of EH EVOO for one year resulted in significant improvements in several MS symptoms including visuospatial memory and processing speed, and an improvement in functions related to the frontal lobes, such as mental flexibility and adaptation to the environment, when compared to untreated patients. In this line, EVOO was suggested to have an important role in neuroprotection as it prevents cognitive decline in humans ^[103]. The mediterranean diet, which is rich in EVOO, has been shown to prevent cognitive de-cline in Alzheimer’s disease in the elderly population ^[104].

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