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European Journal of Clinical Nutrition (2005) 59, 1347–1361
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REVIEW
Antioxidants and polyunsaturated fatty acids in
multiple sclerosis
ME van Meeteren1, CE Teunissen2, CD Dijkstra2 and EAF van Tol1*
1
Department of Biomedical Research, Numico Research BV, Wageningen, The Netherlands; and 2Department of Molecular Cell Biology
and Immunology, VU University Medical Center, Amsterdam, The Netherlands
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). Oligodendrocyte damage and
subsequent axonal demyelination is a hallmark of this disease. Different pathomechanisms, for example, immune-mediated
inflammation, oxidative stress and excitotoxicity, are involved in the immunopathology of MS. The risk of developing MS is
associated with increased dietary intake of saturated fatty acids. Polyunsaturated fatty acid (PUFA) and antioxidant deficiencies
along with decreased cellular antioxidant defence mechanisms have been observed in MS patients. Furthermore, antioxidant
and PUFA treatment in experimental allergic encephalomyelitis, an animal model of MS, decreased the clinical signs of disease.
Low-molecular-weight antioxidants may support cellular antioxidant defences in various ways, including radical scavenging,
interfering with gene transcription, protein expression, enzyme activity and by metal chelation. PUFAs may not only exert
immunosuppressive actions through their incorporation in immune cells but also may affect cell function within the CNS. Both
dietary antioxidants and PUFAs have the potential to diminish disease symptoms by targeting specific pathomechanisms and
supporting recovery in MS.
European Journal of Clinical Nutrition (2005) 59, 1347–1361. doi:10.1038/sj.ejcn.1602255; published online 24 August 2005
Keywords: multiple sclerosis; antioxidants; polyunsaturated fatty acids; dietary supplementation; demyelination; remyelination
Introduction
Pathological mechanisms involved in multiple sclerosis
(MS)
MS is a chronic demyelinating disease of the central nervous
system (CNS). Oligodendrocytes, the myelin-forming cells
of the CNS, are target cells in the pathogenesis of MS. At
present the cause of onset of MS is unknown, but activated
T cells and macrophages are thought to be involved in
*Correspondence: EAF van Tol, Department of Biomedical Research,
Numico Research B.V., PO Box 7005, 6700 CA Wageningen, The
Netherlands.
E-mail: [email protected]
Guarantor: EAF van Tol.
Contributors: MEvM initiated this study together with CD and EvT.
The paper was written by MEvM with contributions from CD, CT and
EvT. CD contributed with her expertise on immunopathology and
experimental models of MS. EvT is responsible for an experimental
research programme in clinical nutrition and contributed his
expertise on antioxidants and PUFAs. CT contributed her expertise
on experimental research in MS in particular on cholesterol and
statins in neuropathological processes. All authors substantially
contributed to and approved the manuscript.
Received 21 September 2004; revised 31 May 2005; accepted 29 June
2005; published online 24 August 2005
demyelination through various mechanisms. New insights
suggest oligodendrocyte apoptosis to be a primary event
accompanied by microglial activation (Barnett & Prineas,
2004). Subsequently, T cells and macrophages become
activated and migrate into the lesion area. The important
pathological mechanisms involved in MS include immunemediated inflammation (Owens, 2003), oxidative stress
(Evans, 1993; Knight, 1997; Smith et al, 1999) and excitotoxicity (Matute et al, 2001). These mechanisms may all
contribute to oligodendrocyte and neuronal damage and
even cell death, hence promoting disease progression.
Immune-mediated inflammation. MS has an autoimmune
inflammatory component mediated by myelin-specific
CD4 þ T cells. However, recent studies have challenged this
concept by indicating a role for other immune cells
(Hemmer et al, 2002). Recently, axonal damage has been
identified as an early hallmark of MS (Kornek & Lassmann,
2003) involving CD8 þ T cells and antibodies (Owens, 2003).
Inflammatory cells and mediators induce axonal loss as well
as demyelination. In contrast, inflammation may improve
MS pathology (Kieseier & Hartung, 2003). As different
immunopathological pathways are involved in different
Antioxidants and PUFAs in MS
ME van Meeteren et al
1348
subgroups of patients (Lassmann, 1999; Kornek & Lassmann,
2003), the specific role of antioxidants and polyunsaturated
fatty acids (PUFAs) deserves further clarification.
Oxidative stress. Reactive oxygen species (ROS) are implicated as mediators of demyelination and axonal damage
in both MS and experimental allergic encephalomyelitis
(EAE) (Lin et al, 1993; Cross et al, 1997; van der Goes et al,
1998), an animal model of MS. Local ROS levels increase
dramatically under inflammatory conditions and exhaust
the antioxidant defence potential within the lesions (Smith
et al, 1999). These excessive ROS levels are primarily
generated by activated macrophages and microglia (Fisher
et al, 1988; Hartung et al, 1992). ROS can damage lipids,
proteins and nucleic acids of cells, resulting in disturbed
mitochondrial function which may induce cell death
(Bolanos et al, 1997; Merrill & Scolding, 1999). Oligodendrocytes, including the extensive myelin sheaths they
produce, are particularly vulnerable to oxidative stress
(Smith et al, 1999). Oxidative stress in vivo can selectively
cause oligodendrocyte cell death, resulting in demyelination. ROS may also damage the myelin sheath by promoting
its attack by macrophages (van der Goes et al, 1998).
Furthermore, oxidative stress is involved in the cascade of
events leading to neuronal cell death (Emerit et al, 2004).
Excitotoxicity. Oligodendrocytes are highly vulnerable to
excitotoxic signals mediated by glutamate receptors (Oka
et al, 1993; Matute et al, 2001). During inflammation,
activated immune cells release large amounts of glutamate
(Piani & Fontana, 1994). Oligodendrocytes contribute to the
CNS glutamate homeostasis by means of their own transporters. However, alterations in glutamate homeostasis can
result in overactivation of glutamate receptors and subsequent excitotoxic oligodendroglial death (Matute et al,
2001). Demyelinated lesions caused by excitotoxins can
be similar to those observed in MS, and glutamate-induced
excitotoxicity may cause axonal loss. Together with the
beneficial effects of glutamate receptor antagonists in EAE,
these findings indicate that oligodendrocyte excitotoxicity
plays a role in the pathogenesis of MS (Pitt et al, 2000).
Interaction between different pathological mechanisms
in MS
In CNS disease oxidative stress has been linked with other
pathogenic mechanisms such as excitotoxicity (Léwen et al,
2000). High levels of extracellular glutamate inhibit the
cellular availability of cystine. This results in the depletion of
glutathione and induces a form of cell injury called oxidative
glutamate toxicity (Schubert & Piasecki, 2001). Excitotoxicity frequently leads to a prooxidant condition. Both
excitotoxic and ‘oxidotoxic’ states result from the failure of
normal compensatory antiexcitatory and antioxidative
mechanisms to maintain cellular homeostasis (Bondy &
LeBel, 1993). Furthermore, oxidative toxicity and excitotoxiEuropean Journal of Clinical Nutrition
city are closely interactive and excitotoxicity likely constitutes the final common pathway of neuronal and axonal loss
(Lipton & Rosenberg, 1994).
Treatment strategies in MS
Remyelination occurs during the early phases of disease,
whereas this is rare at more progressed stages (Lassmann et al,
1997). Remyelination requires the presence of oligodendrocyte progenitors in the vicinity of the lesion area and involves adequate control by specific growth factors (Woodruff
& Franklin, 1997). Differentiation of progenitors into
mature myelin-forming oligodendrocytes is accompanied
by extensive formation of new oligodendrocyte cell membranes to re-insulate demyelinated axons. It is suggested that
dietary compounds such as PUFAs may support this process
(Di Biase & Salvati, 1997).
At present, no pharmaceutical or other therapy exists that
can confer prolonged remission in MS and therapeutic
agents are only partially effective. Their long-term beneficial
effects are uncertain and often detrimental side-effects have
been reported (Johnson et al, 1995; Filippini et al, 2003). This
review addresses the role of nutrition in MS. We discuss the
potential of directly acting nonenzymatic antioxidants for
dietary supplementation and elaborate on the role of longchain n-6 and n-3 PUFAs in immunosuppression, cellular
function and remyelination.
Role of nutrition in MS
Correlation of dietary pattern with the incidence of MS
The etiology of MS is largely unknown, although genetic and
environmental factors are believed to be involved. Diet is an
important subject of etiologic research in this respect. Swank
(1950) found a correlation between high dietary intake of
saturated fatty acids and the incidence of MS. Meta-analysis
of epidemiological studies has demonstrated a relation
between MS mortality and dietary fat (Esparza et al, 1995).
Saturated fatty acids, animal fat and animal fat without fish
fat correlate positively with MS mortality. An increased risk
for MS was found to be associated with high energy and
animal food intake (Ghadirian et al, 1998). The same study
also revealed a protective effect of other nutrients, including
vegetable protein, dietary fibre, cereal fibre, vitamin C,
thiamine, riboflavin, calcium and potassium. In contrast,
another study found no associations between intake of fruits
and vegetables, multivitamins and vitamins C and E, with
the risk of MS in women (Zhang et al, 2001).
Antioxidant deficiencies in MS
It is not clear at present if antioxidant deficiency in MS is
constitutive or due to excessive antioxidant consumption
to cope with oxidative stress. Antioxidant deficiencies may
develop during the course of MS as a result of chronic
inflammation that is accompanied by increased oxidative
Antioxidants and PUFAs in MS
ME van Meeteren et al
1349
stress. Levels of the antioxidants a-tocopherol, b-carotene,
retinol and ascorbic acid were decreased in the sera of MS
patients during an attack (Besler et al, 2002). This was also
illustrated by increased oxidative burden, as reflected by
lipid peroxidation. Another study showed lipoprotein oxidation being an important sign of oxidative stress during the
course of MS. Therefore, in vitro measurements of plasma
oxidation kinetics as an indication for lipoprotein oxidation
may be an additional tool in the clinical diagnosis of MS
(Besler & Comoglu, 2003).
The chemical composition of human cerebrospinal fluid
(CSF) is considered to reflect brain metabolism. CSF vitamin
E levels were not significantly different between MS patients
during exacerbations as compared to controls, while serum
levels of vitamin E indeed were lower in MS patients
(Jimenez-Jimenez et al, 1998). In MS plaques, levels of
glutathione (GSH) and vitamin E were significantly decreased as compared to adjacent and distant white matter
(Langemann et al, 1992). From these studies, it can be
concluded that systemic, CSF and brain tissue levels of
several antioxidants indeed are altered in MS. Therefore,
antioxidant therapy may be beneficial in restoring these
deficiencies and supporting the antioxidant defence capacity
of MS patients.
PUFA deficiencies in MS
In a double-blind and randomised study, no differences were
observed between MS patients and healthy controls with
regard to fat malabsorption (Wong et al, 1993). Nevertheless,
there were deficiencies of essential PUFAs (ie PUFAs of the
n-3 and n-6 series; Figure 1) in both plasma lipids and
erythrocytes (Cherayil, 1984; Cunnane et al, 1989; Holman
et al, 1989). Plasma linoleic acid (LA; 18:2n-6) was normal,
and g-linolenic acid (GLA; 18:3n-6) increased in MS patients,
but subsequent n-6 acids were subnormal, indicating
impairment of chain elongation (Holman et al, 1989). In
addition, the content of all n-3 fatty acids was subnormal
and PUFA deficiency was compensated mass-wise by an
increase in saturated fatty acids. In red blood cells and
adipose tissue of mild inactive MS patients, there was a
significant reduction in eicosapentaenoic acid (EPA; 20:5n-3),
and an increase in both dihomo-g-linolenic acid (DGLA;
20:3n-6) and stearidonic acid (SA; 18:4n-3) (Nightingale et al,
1990). In contrast, there were no detectable EPA levels in the
adipose tissue of MS patients and healthy individuals.
However, whereas in MS patients docosahexaenoic acid
(DHA; 22:6n-3) was not detectable, 40% of healthy controls
had significant levels varying from 0.1 to 0.3% of the total
estimated fatty acid. No reduction in LA was observed in red
blood cells or adipose tissue of MS patients (Nightingale et al,
1990). In MS plaques, the lipid and fatty acid composition
appears to be altered (Wilson & Tocher, 1991). The cause of
these PUFA deficiencies is not entirely clear and may involve
metabolic and nutritional alterations.
Figure 1 Metabolic pathways of desaturation and elongation of
n-6 and n-3 fatty acids. The different families of fatty acids may
compete in the desaturation process. n-6 and n-3 fatty acids in
phospholipids are precursors of prostaglandin E (PGEx) synthesis. LA,
linoleic acid; GLA, g-linolenic acid; DGLA, dihomo-g-linolenic acid;
AA, arachidonic acid; DTA, docosatetraenoic acid; DPA, docosapentaenoic acid; LNA, a-linolenic acid; SA, stearidonic acid; EPA,
eicosapentaenoic acid; DHA, docosahexaenoic acid.
Intervention studies
The effect of PUFA supplementation in MS has extensively
been investigated, but with equivocal outcome. The evaluation of three double-blind trials with LA (n-6) in early MS
showed reduction of the severity and duration of relapses
(Dworkin et al, 1984). Fish oil supplemented together with
vitamins and dietary counselling improved the clinical
outcome in newly diagnosed MS patients (Nordvik et al,
2000). On the other hand, a clinical trial with n-3 PUFA
treatment in acute relapsing MS showed no significant
differences (Bates et al, 1989). However, there was a
favourable trend of the n-3 PUFAs-treated group on parameters like overall deterioration, as well as the frequency,
severity and duration of relapses. The discrepancies between
these studies may be explained by different criteria for
patient selection (clinical subtype of MS), and different
disability scores at the start of the study (Gallai et al, 1992).
High-dose antioxidant supplementation with sodium
selenite, vitamin C and vitamin E has been tested in MS
patients and appeared to be safe (Mai et al, 1990). Moreover,
low blood GSH peroxidase activity that was associated with
disease activity could be increased by the antioxidant
administration (Mai et al, 1990). Similarly, antioxidant
treatment with selenium, vitamin C and E restored GSH
levels as well as the GSH peroxidase activity in erythrocytes
of MS patients (Jensen & Clausen, 1986).
Oxidative stress and antioxidants
Reactive oxygen and nitrogen species
ROS and reactive nitrogen species (RNS) play an important
role during the pathogenesis of MS. ROS are produced
primarily by mitochondria as a by-product of normal cell
metabolism during conversion of molecular oxygen (O2)
(Figure 2). The products formed by the mitochondrial
European Journal of Clinical Nutrition
Antioxidants and PUFAs in MS
ME van Meeteren et al
1350
Figure 2 The main reactive oxygen and nitrogen species produced
during normal cell metabolism and oxidative stress (OK
2 , superoxide; NO, nitric oxide; OONO, peroxynitrite; H2O2, hydrogen
peroxide; HOK, hydroxyl radical). Overview of interactions and the
converting enzymes that are involved.
K
respiratory chain include superoxide radical (O
2 ), hydroK
gen peroxide (H2O2) and hydroxyl radical (HO ). Transfer of
an electron to oxygen by cytochrome c oxidase and flavin
K
(Léwen et al, 2000).
enzymes results in production of O
2
K
into
The enzyme superoxide dismutase (SOD) converts O
2
H2O2 and O2. However, during oxidative burst, activated
macrophages produce elevated levels of ROS and RNS by
upregulation of NADPH oxidase and inducible nitric oxide
K
and NO
(NO) synthase (iNOS), respectively producing O
2
K
and NO form
radicals (Hartung et al, 1992). Together, O
2
the very harmful peroxynitrite (ONOO). Peroxynitrite
decays to yield oxidising and nitrating species that react in
complex ways with different relevant biomolecules. These
reactive species not only induce lipid peroxidation or affect
DNA structure, they also react with cellular proteins by
tyrosine nitration (Smith et al, 1999; Torreilles et al, 1999).
K
detoxification by
H2O2 is formed as a by-product of the O
2
SOD during episodes of oxidative stress. The largest portion
of H2O2 is converted into H2O and O2 by catalase, but some
of it may escape into the cell when the H2O2-metabolising
capacity of catalase is insufficient. Through Fenton chemistry,
H2O2 will then be converted to HOK, the most reactive
oxygen radical (Figure 2). Under certain conditions, formation of HOK will be perpetuated through the nonenzymatic
Haber–Weiss reaction, requiring free intracellular iron and
K
or ascorbate (Halliwell, 1992).
O
2
European Journal of Clinical Nutrition
Antioxidant treatment in experimental models of MS
Activated macrophages and microglia may produce high
levels of NO and H2O2 that are involved in the pathogenesis
of EAE (Lin et al, 1993; Ruuls et al, 1995; Minghetti & Levi,
1998). Treatment of EAE with catalase, a H2O2 scavenger,
markedly suppressed disease severity (Ruuls et al, 1995). In
the same model, local augmentation of catalase by viralmediated gene delivery suppressed optic neuritis (Guy et al,
1998). In contrast, intraperitoneal administration of SOD, an
enzyme that detoxifies superoxide, had no effect in EAE in
rats (Ruuls et al, 1995). Uric acid is a natural scavenger of
peroxynitrite that inhibits clinical signs in EAE and MS
patients (Hooper et al, 1998). Evaluation of more than 20
million patient records revealed MS and gout (hyperuricemic
syndrome) to be mutually exclusive diseases, suggesting
hyperuricaemia to protect against MS (Hooper et al, 1998;
Spitsin et al, 2002). Furthermore, oral administration of the
oxidant scavenger N-acetylcysteine (NAC) inhibited EAE
(Lehmann et al, 1994). Desferrioxamine, an iron chelator
(Pedchenko & LeVine, 1998), suppressed the development of
EAE, whereas iron-deficient mice failed to develop EAE
(Grant et al, 2003). It was proposed that the mechanism of
EAE inhibition in iron-deficient mice involves the delivery
and metabolism of iron for optimal CD4 þ T-cell development (Grant et al, 2003). Some investigators have shown
iNOS inhibition as well as NO scavenging to suppress EAE
(Cross et al, 1994; Zhao et al, 1996; Hooper et al, 1997;
Jolivalt et al, 2003), whereas others have shown iNOS
inhibition (O’Brien et al, 1999, 2001) or NO donor (Xu
et al, 2001) to aggravate or ameliorate EAE, thus not
clarifying the exact role for NO (Willenborg et al, 1999).
Cellular antioxidant defence
The cellular antioxidant defence mechanisms can be classified into two major groups: enzymatic (eg, catalase, SOD,
hydrogen peroxidase), and nonenzymatic or low-molecularweight antioxidants (Gilgun-Sherki et al, 2004). The latter
group can be further classified into directly acting antioxidants
(eg, scavengers and chain breaking antioxidants) and
indirectly acting antioxidants (eg, chelating agents). This
review focussed on directly acting nonenzymatic antioxidants, for example, vitamin C and E, thiol-based antioxidants, flavonoids and curcumin.
Vitamin C. Vitamin C (ascorbic acid) is a water-soluble
antioxidant found throughout the body as the ascorbate
anion. Ascorbate is abundantly present in the CNS. Humans
have lost the ability to synthesise ascorbate, but dietary
sources like fruit and vegetables are widely available and
ascorbate is readily absorbed from the gut (Kallner et al,
1977). The high intracellular ascorbate level in the CNS
underlines its important function. Ascorbate is part of the
brain antioxidant network (Figure 3) and acts as an
intracellular antioxidant in the defence against highly
reactive free radicals (Cohen, 1994). Ascorbate operates in
Antioxidants and PUFAs in MS
ME van Meeteren et al
1351
Figure 3 The antioxidant network showing the interaction between vitamin E, vitamin C and thiol redox cycles, as well as their cellular
localisation; adapted from Packer et al (2001). ROS and products of lipid peroxidation present in the cytosol or cell membrane may be detoxified
by this system. ROOK, peroxyl radical; ROK, alkoxyl radical.
concert with other low-molecular-weight molecules, including GSH and vitamin E, as well as with antioxidant
enzymes such as SOD and GSH peroxidase (Cohen, 1994).
Ascorbate concentrations in plasma are about 50 mM
(Hornig, 1975), while the concentration in neurons is
estimated to be 10 mM and levels of 1 mM in glia (Rice &
Russo-Menna, 1998). The brain has a relative high rate of
oxidative metabolic activity and low levels of protective
antioxidant enzymes, for example, catalase and GSH peroxidase (Evans, 1993). Under normal physiological conditions, oxidation of ascorbate into dehydroascorbate can be
reduced by GSH. In this way, ascorbate is continuously
regenerated. However, when high levels of ROS are produced, oxidative stress will occur in the context of insufficient antioxidative capacity to regenerate ascorbate. During
active disease in MS, ROS scavenging by ascorbate and other
molecules of the antioxidant network might deplete levels of
these defence molecules (Besler et al, 2002).
Vitamin C can also increase iron-catalysed oxidation
through the Fenton reaction, generating hydroxyl radicals
(Nappi & Vass, 1997) that are very reactive and detrimental
to various cell structures by oxidation of DNA, RNA, proteins
and membrane lipids (Richter et al, 1988; Halliwell, 1992).
Vitamin C treatment was not found to be protective in
murine EAE and the authors explained this by the ambivalent role of vitamin C during oxidative stress (Spitsin et al,
2002). The latter should be taken into account when vitamin
C supplementation to MS patients is considered.
Vitamin E. Where ascorbate is predominantly found in the
cytosol, vitamin E is localised exclusively within the lipid
part of cell membranes (Figure 3). Vitamin E is an important
antioxidant that can interrupt the propagation of free radical
chain reactions (Vatassery, 1998a). Vitamin E occurs in at
least eight different isoforms: a-, b-, g- and d-tocopherols and
a-, b-, g- and d-tocotrienols. Although the antioxidant
activity of tocotrienols is higher than that of tocopherols,
tocotrienols have a lower bioavailability after oral ingestion
(Packer et al, 2001). Vitamin E can be found in our diet in
vegetable oils like sunflower and olive oil, non-citrus fruits,
nuts and seeds. It is absorbed together with lipids in
the intestine and released into the circulation through
chylomicrons.
In contrast to vitamin C, levels of vitamin E in the brain
are not remarkably different from those in other organs
(Vatassery, 1998a). Vitamin E levels in the CSF are about
1000 times lower as compared to serum levels as a
consequence of the low lipid concentration in the CSF,
which is o0.2% of the concentration in serum (Vatassery
et al, 1991). In the blood of MS patients, a-tocopherol levels
are lowered during exacerbation (Karg et al, 1999; Besler et al,
2002), whereas a-tocopherol levels in CSF during MS
exacerbation are not different from controls (JimenezJimenez et al, 1998).
Vitamin C and E work closely together in the antioxidant
network at the interface of cytosol and cell membrane,
where oxidised vitamin E can be regenerated by vitamin C
European Journal of Clinical Nutrition
Antioxidants and PUFAs in MS
ME van Meeteren et al
1352
(Vatassery, 1998a) (Figure 3). Rare genetic mutations may
lead to vitamin E deficiencies, whereas vitamin E deficiency
due to dietary restriction has not been reported in humans
(Brigelius-Flohe et al, 2002). The antioxidant efficiency of
a-tocopherol depends on its ability to react mainly with the
chain-initiating or chain-propagating lipid radicals during
lipid peroxidation (Fukuzawa et al, 1985). Furthermore, atocopherol efficiently detoxifies hydroxyl, perhydroxyl and
superoxide free radicals (Fukuzawa & Gebicki, 1983). aTocopherol has been demonstrated to protect rat brain
subcellular fractions against peroxynitrite-induced oxidative
damage (Vatassery et al, 1998b). However, g-tocopherol
seems to be more effective than a-tocopherol in trapping
NO radicals (Christen et al, 1997). This discrepancy in
activity may be related to their structural properties. aTocopherol also exerts non-antioxidant properties, for
example, modulation of cell signalling, regulation of
transcription, modulation of immune function and induction of apoptosis (Brigelius-Flohe et al, 2002). Taken together,
vitamin E isoforms are important in the protection of CNS
cells through antioxidative and nonantioxidative mechanisms. However, it is difficult to achieve high plasma atocopherol concentrations irrespective of the amount or
duration of dietary supplementation (Dimitrov et al, 1991).
In addition, feeding studies in healthy mice revealed a tissuespecific distribution of tocopherols and tocotrienols. Brain
vitamin E contained only a-tocopherol and traces of
g-tocopherol, where a- and g-tocotrienols were both undetectable, suggesting a specific transport mechanism for
a-tocopherol to cross the blood–brain barrier (BBB) (Podda
et al, 1996).
Thiol-based antioxidants
N-acetylcysteine (NAC). NAC belongs to the group of
thiol-based antioxidants, which also includes a-lipoic acid
and GSH (Deneke, 2000). It is widely used as a drug because
of its ability to scavenge H2O2, hydroxyl radicals and
hypochlorus acid, and it acts as a precursor for GSH synthesis
(Wernerman & Hammarqvist, 1999). NAC may increase
intracellular cysteine and subsequent GSH levels (Deneke,
2000). The molecular mechanism of NAC was recently
reviewed (Zafarullah et al, 2003). NAC affects transcription
factors, apoptosis and cell survival, all of which are
important targets in treating neurodegenerative diseases.
Clinical use of NAC has shown replenishment of GSH
levels in HIV-positive (Herzenberg et al, 1997) and cystic
fibrosis patients (Meyer et al, 1995). NAC usage has been
suggested for neurodegenerative disorders like Alzheimer’s
disease or Parkinson’s disease (Deigner et al, 2000), but there
are no clinical studies supporting its use in MS. Interestingly,
oral administration of NAC did inhibit acute EAE in mice
(Lehmann et al, 1994) and recent data revealed that NAC
amide protects against EAE by scavenging ROS and reducing
matrix metalloproteinase-9 (MMP-9) activity (Offen et al,
2004).
European Journal of Clinical Nutrition
In vitro data have shown that cultured oligodendrocytes
were protected against tumor necrosis factor (TNF)-ainduced toxicity by NAC (Cammer, 2002). In addition,
treatment with NAC partially suppressed virus-stimulated
production of NO and TNF-a by astrocytes (Molina-Holgado
et al, 1999), and NAC has been shown to protect neuronal
cells from apoptosis (Deigner et al, 2000). NAC inhibited
TNF-a-mediated apoptosis in rat primary oligodendrocytes
by increasing intracellular GSH levels (Singh et al, 1998) and
inhibited NO production in lipopolysaccharide-stimulated
macrophages, C6 glial cells and primary astrocytes (Pahan
et al, 1998).
Glutathione. GSH has important intracellular antioxidant
defence and scavenging capacities, and can be found in
millimolar concentrations in most tissues (Wernerman &
Hammarqvist, 1999). In contrast to ascorbate, which is
highly concentrated in neurons, GSH is localised preferentially in glia cells (Rice & Russo-Menna, 1998). GSH can act
as a cofactor for the enzymatic GSH peroxidase reaction by
which cells convert H2O2 or lipid peroxides to the less toxic
H2O or lipid hydroxyl compounds. Oxidised GSH (GSSG), a
product of this reaction, is then recycled into GSH by GSH
reductase. GSH can also react directly with oxidants and
other radicals (Deneke, 2000) (Figure 3).
In MS patients, during exacerbation blood levels of
oxidised GSH were elevated, while levels of reduced GSH
were increased during exacerbation and remission (Karg et al,
1999). This could reflect a compensatory mechanism to
defend cells against oxidative stress. In another study,
decreased levels of GSH were measured in plaques from
MS patients (Langemann et al, 1992). Moreover, decrease of
reduced GSH and increase oxidised GSH and S-nitrosothiols
were found in CSF samples of MS patients (Calabrese et al,
2002). Oral administration of GSH results in poor systemic
bioavailability (Kidd, 2001). Therefore, NAC supplementation seems preferable in a low GSH status since this
compound has superior bioavailability. It should be noted
that restoring GSH levels via NAC supplementation could
be less effective in case GSH peroxidase enzyme activity is
impaired. The latter has been described in blood-derived
lymphocytes and erythrocytes from MS patients (Jensen &
Clausen, 1986; Mai et al, 1990).
a-Lipoic acid. a-Lipoic acid and its reduced form dihydrolipoic acid (DHLA) are thiol-based antioxidants. Meat is an
important source of a-lipoic acid, which is absorbed from
the gastrointestinal tract (Harrison & McCormick, 1974), but
can also be synthesised (Carreau, 1979). a-Lipoic acid can
interfere with lipid peroxidation by competing for free
transition metals as a chelator (Muller & Menzel, 1990)
and by scavenging hydroxyl radicals (Suzuki et al, 1991). On
the other hand, DHLA can scavenge peroxyl radicals (Kagan
et al, 1992). Both compounds are capable of scavenging
superoxide radicals (Suzuki et al, 1991) and are integrated
in the antioxidant network (Figure 3). DHLA is capable of
Antioxidants and PUFAs in MS
ME van Meeteren et al
1353
reducing GSSG to GSH and can regenerate ascorbate, either
by direct reaction with dehydroascorbate or through reduction of GSSG to GSH, which is also a reducing agent for
ascorbate (Packer et al, 1995).
The beneficial effects of a-lipoic acid in EAE were
associated with its nonantioxidative capacity (Morini et al,
2004). Furthermore, a-lipoic acid was effective in treating
EAE by inhibiting T-cell trafficking into the spinal cord by
inhibiting matrix metalloproteinase activation (Marracci
et al, 2002). Furthermore, it has been precised that a-lipoic
acid, like NAC (Offen et al, 2004), reduces MMP-9 activity,
whereas DHLA does not (Marracci et al, 2004).
The antioxidant capacity of a-lipoic acid was also tested
in vitro on OLN-93 oligodendroglia. a-Lipoic acid
elevated cell viability and decreased protein oxidation after
H2O2-induced oxidative stress (Ernst et al, 2004). Myelin
phagocytosis by macrophages, which is a ROS-mediated
process and an important immunological event in MS
pathology, could also be decreased by a-lipoic acid (van der
Goes et al, 1998).
Considering the above, NAC, a-lipoic acid and DHLA
might prevent ROS-induced CNS demyelination and
axonal damage in MS patients. However, the relevance of
thiol-based dietary supplementation and their potential
role in antioxidant therapy for MS patients remains to be
established.
Flavonoids. Flavonoids belong to a group of at least 4000
naturally occurring compounds found in fruit, vegetables,
grains, tea and wine (Manach et al, 2004). Flavonoids share a
common polyphenolic structure consisting of two aromatic
rings that are bound together by three carbon atoms that
form an oxygenated heterocycle. There are six different
subclasses of flavonoids depending on the type of heterocycle involved: flavonols, flavones, isoflavones, flavanones,
anthocyanidins and flavanols.
The health effects of polyphenols depend on intake and
bioavailability (Manach et al, 2004). By using the data of the
Dutch National Food Consumption Survey 1987–1988, the
daily human intake of a subset of five anticarcinogenic
flavonoids was estimated to be around 23 mg/day (Hertog
et al, 1993). The intake of those antioxidant flavonoids still
exceeded that of the antioxidants b-carotene and vitamin E.
Thus, flavonoids seem to represent an important source of
antioxidants in the human diet.
Flavonoids derived from natural sources occur mainly
as glycosides, that is, covalent binding of a sugar moiety
to the aglycon. The glycoside forms of the flavonoid
quercetin are more readily absorbed from the intestine
than its aglycon (Hollman & Katan, 1998). Owing to their
hydrophilicity, flavonoids are likely to be concentrated
at the interface between the phospholipid bilayers and
cytosol, where they can prevent lipid peroxidation. Over
the years, flavonoids have appeared to be safe dietary
compounds with a broad range of biological activities
(Middleton et al, 2000).
The strong antioxidant activity of flavonoids is attributed
to the polyphenolic molecular structure and depends on
their interaction with the cell membrane (Saija et al, 1995).
Flavonoids can prevent oxidative stress by direct scavenging
of free radicals. In this way, flavonoids become oxidised and
form a more stable and less reactive radical. Luteolin and
quercetin belong to the flavone and flavonol group,
respectively, and both prevent H2O2-induced oxidative stress
in oligodendroglia (van Meeteren et al, 2004). Some
flavonoids, for example, quercetin, can redoxcycle (Hodnick
et al, 1986) and have been shown to be pro-oxidants by the
reduction of Fe3 þ (Canada et al, 1990). This renders these
compounds less suitable for therapeutical application (van
Acker et al, 1996).
Flavonoids are also very potent NO radical scavengers (van
Acker et al, 1995) and inhibit the NO production by activated
macrophages (van Meeteren et al, 2004), microglia (Merrill
et al, 1993) and astrocytes (Soliman & Mazzio, 1998).
Flavonoids act at other cellular levels, for example, inhibition of iNOS enzyme activity (Kobuchi et al, 1999), iNOS
protein expression (Kim et al, 1999; Liang et al, 1999; van
Meeteren et al, 2004) and transcription of nuclear factor kB
(NFkB) (Choi et al, 2003). Interactions between flavonoids
and the antioxidant network have been described. Flavonoids may spare ascorbate from oxidation by metal chelation
or by free radical scavenging (Kandaswami & Middleton,
1994).
Some flavones and flavonols such as apigenin, kaempferol
and naringenin can have estrogenic effects (Miksicek, 1995),
whereas others exert antiestrogenic properties (Virgili et al,
2004). Based on the observation that MS patients have fewer
relapses during pregnancy and that the disease is commonly
exacerbated in the first few months after delivery, estrogen
has been suggested to ameliorate disease progression
(Confavreux et al, 1998). In addition, oral administration
of estrogen suppressed clinical symptoms in murine EAE and
inhibited the recruitment of inflammatory cells into the CNS
(Subramanian et al, 2003). Interestingly, a recent report by
Muthian and Bright (2004) described quercetin, a flavonoid
phytoestrogen, also to ameliorate EAE.
The capacity of various flavonoids to inhibit phagocytosis
in vitro correlates with their antioxidative potency, and is in
line with the requirement of ROS for myelin phagocytosis by
macrophages (Hendriks et al, 2003). Moreover, oral administration of luteolin effectively reduces clinical symptoms in
chronic EAE (Hendriks et al, 2004).
Curcumin. Curcumin (diferuloyl methane) is a naturally
occurring compound isolated from the rhizomes of the plant
Curcuma longa and frequently used as a yellow pigment in
curry. Curcuma longa has an extensive history in traditional
medicine and dietary use in Asian countries (Eigner &
Scholz, 1999). The food additive curcumin is a natural
product and its safety was supported by the nontoxic
consumption of up to 110 mg/day in humans and up to
5 g/day in rats (Commandeur & Vermeulen, 1996).
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Curcumin has many biological effects, including antiinflammatory, antioxidant, anticarcinogenic, antiviral and
anti-infectious activity (Joe et al, 2004). It protects against
H2O2-induced oxidative stress in renal epithelial cells (Cohly
et al, 1998) and inhibits the production of superoxide
radicals, H2O2 and NO by macrophages (Joe & Lokesh,
1994; van Meeteren et al, 2004) and astrocytes (Soliman &
Mazzio, 1998). Although antioxidative effects cannot be
excluded, the inhibitory effect of curcumin on clinical and
pathological symptoms in murine EAE were attributed to
blocking of IL-12 signalling through the Janus kinase–STAT
pathway in T cells (Natarajan & Bright, 2002). In addition, in
a mouse model of Alzheimer-like pathology, curcumin was
found to decrease inflammation and oxidative damage in
the brain (Lim et al, 2001).
Polyunsaturated fatty acids (PUFAs)
From the human diet, LA and a-linolenic acid (LNA; 18:n-3)
are required as substrates for the synthesis of the essential n6 and n-3 long-chain fatty acids (Figure 1). It has been
established that changes in dietary fat intake alter PUFA
incorporation in cell membranes (Clandinin et al, 1991),
where these compounds have different effects. They may
induce immunosuppression through their actions on the
arachidonic acid (AA; 20:4n-6) pathway (Meydani, 1996).
Membrane incorporation of PUFAs may change cellular
susceptibility to lipid peroxidation, alter membrane fluidity,
receptor function, enzyme activity, and influence the
production of lipid mediators (Wu & Meydani, 1998). At
the intracellular level, PUFA incorporation may change
the receptor-mediated stimulation of gene products or
the transport of gene products from the nucleus (Clandinin
et al, 1991).
PUFAs in experimental models of MS
Oral administration of essential fatty acids (EFA) suppressed
EAE (Mertin & Stackpoole, 1978). This effect could be
abolished by indomethacin, indicating prostaglandins
(PGs) as mediators of this effect (Mertin & Stackpoole,
1978). In addition, clinical signs of EAE could be abrogated
by oral administration of GLA and LA-rich oils (Harbige et al,
1995). In another study, oral supplementation with n-6 fatty
acid GLA from Borago officinalis ameliorated both acute
and chronic disease in EAE (Harbige et al, 2000). This was
associated with increased DGLA and AA in the cell
membrane, gene transcription, production of prostaglandin
E2 (PGE2) and secretion of TGF-b1. The increased levels of
PGE2 were associated with an altered balance of TH1 and
TH2-type cytokines, thus preventing T-cell-mediated autoimmune disease (Harbige et al, 2000). Intraperitoneal
administration of a mixture of essential fatty acids, containing LA (n-6) and LNA (n-3), improved biochemical and
cognitive functions in EAE rats by improving neuronal
European Journal of Clinical Nutrition
communication at brain synaptosomes as compared to
nontreated EAE animals (Yehuda et al, 1997).
Immune modulation and CNS cell function
As precursors for inflammatory mediators, for example, PGs,
tromboxanes (TXs) and leukotrienes, PUFAs can affect the
immune response. The fatty acids of the n-3 family give rise
to PGs of the ‘3’ series, while those from the n-6 family give
rise to the ‘1’ and ‘2’ series (Figure 1). As a result of changes in
this eicosanoid production, PUFAs can affect cytokine
expression (Grimble, 1998). N-3 PUFAs may suppress proinflammatory TNF-a and IL-1 production and actions, while
n-6 PUFAs have the opposite effect. Indeed, patients with
autoimmune diseases, such as rheumatoid arthritis, inflammatory bowel disease and asthma, responded well to
supplementation with long-chain n-3 fatty acids EPA and
DHA by decreasing disease-associated elevated levels of
cytokines (Simopoulos, 2002). In addition, fish oil supplementation of newly diagnosed MS patients increased the
plasma phospholipid n-3 fatty acids and decreased the n-6
fatty acids, resulting in significant reduction of exacerbations and the EDSS clinical score (Nordvik et al, 2000). Apart
from their immunomodulatory effects, these compounds
may change the PUFA membrane profile of cells within the
CNS, thereby changing brain cell activity.
n-6 PUFAs. Dietary oils derived from plants and seeds are
the main source of n-6 PUFAs. After cellular uptake of LA,
elongation and desaturase enzyme activity can produce
the longer-chain fatty acids, for example, GLA, DGLA and
arachidonic acid (AA; 20:4n-6). During pathological conditions, the release of AA from the cell membrane by
phospholipase A2 activity will be increased, giving rise to
proinflammatory PGs and TXs of the ‘2’ series, that is, PGE2
and tromboxane A2 (TXA2), while DGLA is a precursor of PGs
of the ‘1’ series harbouring anti-inflammatory properties.
In vitro n-6 PUFAs can alter the function of oligodendrocytes by affecting their membrane composition (Soliven &
Wang, 1995). For instance, membrane depolarisation affects
protein phosphorylation of myelin basic protein in oligodendrocytes, an important event in myelination (Takeda &
Soliven, 1997).
n-3 PUFAs. EPA and DHA both belong to the group of n-3
PUFAs. Membrane DHA originates from dietary DHA and by
conversion of dietary LNA with EPA as an intermediate
product (Alessandri et al, 2003). However, DHA can function
as a source of EPA as well through retro-conversion.
Subsequently, EPA can be oxygenated to various eicosanoid
metabolites such as PGE3, PGF3 and TXA3 (Youdim et al,
2000). Fish oil and oily fish are dietary sources both rich in
n-3 PUFAs. High dietary LNA increases the LNA, but not the
DHA contents in brains of suckling rats (Bowen & Clandinin,
2000). Thus, when increased DHA in the brain is required,
DHA itself, and not LNA, should be administered.
Antioxidants and PUFAs in MS
ME van Meeteren et al
1355
Dietary supplementation with a mixture of EPA and DHA
could reduce cytokine secretion and eicosanoid production
in peripheral blood mononuclear cells of relapsing-remitting
MS patients (Gallai et al, 1995).
By competing with AA for the same metabolising enzymes,
EPA and DHA can prevent the formation of leukotriene and
PGE2 synthesis in vitro (Needleman et al, 1979; Lee et al,
1988). It was also shown that OLN-93 oligodendrocytes
enriched with DHA and exposed to H2O2 were more
susceptible to apoptosis than controls (Brand et al, 2001).
This study underlines that membrane lipid composition is
critical in either promoting or preventing apoptotic cell
death (Brand et al, 2001). Moreover, increased incorporation
of very long PUFAs into the cell membrane may result in
increased susceptibility to lipid peroxidation (Song et al,
2000). High tissue and plasma DHA levels in rats due to the
ingestion of DHA-containing oil enhanced membrane
susceptibility to lipid peroxidation and disrupted the antioxidant system. Since this was accompanied by a reduction
of a-tocopherol levels appropriate vitamin E, supplementation should be considered in that case.
Cholesterol and statins
Statins have important biologic effects independent from
their cholesterol-reducing properties that may be beneficial
in neurodegenerative diseases and MS (Stüve et al, 2003a).
Several studies revealed statins to ameliorate clinical signs of
disease in EAE (Stanislaus et al, 2002; Youssef et al, 2002;
Greenwood et al, 2003; Floris et al, 2004). The cholesterollowering effect of statins is regulated through inhibition of
b-hydroxy-b-methylglutaryl-CoA (HMG-CoA) reductase.
This enzyme is involved in cholesterol synthesis and
converts HMG-CoA to L-mevalonate. Through inhibition of
HMG-CoA reductase, statins prevent numerous biological
activities downstream of L-mevalonate (Stüve et al, 2003b).
Statins may also inhibit T-cell entry into the CNS, inhibit
T-cell activation and suppress secretion of numerous inflammatory mediators. Moreover, lovostatin treatment of EAE
rats inhibits macrophage infiltration (Floris et al, 2004) and
simvastatin treatment is beneficial in relapsing–remitting MS
(Vollmer et al, 2004). Statins may be of therapeutic interest
since they can be given orally with a very good safety record
(Polman & Uitdehaag, 2003). Since statins ameliorate MS
through immunomodulatory activity, it seems interesting to
explore whether dietary compounds also interfere with the
cholesterol synthesis.
Curcumin could modulate cholesterol levels in several
experimental models of atherosclerosis (Soudamini et al,
1992; Ramirez-Tortosa et al, 1999). Aside from inhibition of
lipid peroxidation, curcumin also decreased cholesterol
levels in both the serum and brain tissue of mice (Soudamini
et al, 1992). In rats, curcumin significantly decreased the
total and very low-density lipoprotein (VLDL) and LDL
cholesterol plasma concentrations (Kamal-Eldin et al, 2000).
In healthy human subjects, curcumin significantly decreased
serum lipid peroxide levels, increased high-density lipoprotein cholesterol and decreased total serum cholesterol (Soni
& Kuttan, 1992). The underlying mechanism may involve
reduced intestinal uptake of cholesterol (Kamal-Eldin et al,
2000). It has been established that tocotrienol, a vitamin E
isoform, also has hypocholesterolaemic properties through a
mechanism different from HMG-CoA reductase inhibition
(Theriault et al, 1999).
Dietary compounds targeting different
pathomechanisms in MS
a-Lipoic acid and its reduced form DHLA were shown to
inhibit T-cell migration into the spinal cord and suppressed
clinical signs in murine EAE (Marracci et al, 2002). This
finding indicates that these dietary compounds can interfere
with inflammatory mechanisms. In addition, flavonoids and
curcumin were shown to posses anti-inflammatory properties in EAE models (Natarajan & Bright, 2002; Hendriks et al,
2004), suggesting these compounds to have the ability to
reduce MS disease activity. Furthermore, dietary fatty acids
have immunoregulatory activity and the inflammatory
process in autoimmune disease may be an important
mechanistic target for these compounds to modulate disease
activity (Harbige, 1998).
Due to their free radical scavenging, metal chelation and
radical chain reaction-breaking properties, nonenzymatic
antioxidants, for example, vitamin C, vitamin E, thiol-based
antioxidants, flavonoids and curcumin, are important in
prevention of oxidative stress. Moreover, dietary compounds, for example, flavonoids, curcumin, NAC and
vitamin E, can protect neuronal cells against glutamateinduced excitotoxicity (Kobayashi et al, 2000; Sen et al, 2000;
Mazzio et al, 2001). In conclusion, dietary antioxidants and
fatty acids may influence the disease process in MS by
reducing immune-mediated inflammation, oxidative stress
and excitotoxic damage.
CNS bioavailability of dietary antioxidants and
PUFAs
Central availability of dietary compounds or their metabolites is a main obstacle for their use in nutritional therapy of
neurodegenerative diseases, including MS. When dietary
products comprising antioxidants and/or PUFAs are considered for brain diseases, aspects of biotransformation and CNS
availability need to be addressed.
While many compounds have a limited passage through
the BBB, the brain levels of the low-molecular-weight
members of the antioxidant network, for example, vitamin
C and E and GSH, are under strong homeostatic regulation.
NAC, the precursor molecule of GSH, cannot cross the BBB
after exogenous administration (Gilgun-Sherki et al, 2002).
On the other hand, a-lipoic acid that is readily absorbed from
the diet does cross the BBB (Packer et al, 1997).
European Journal of Clinical Nutrition
Antioxidants and PUFAs in MS
ME van Meeteren et al
1356
Flavonoid antioxidants are present in food as glycosides
and the sugar moiety may facilitate their bioavailability in
humans (Hollman et al, 1999). But data on the bioavailability of flavonoids in the brain and other tissues are very
scarce (Manach et al, 2004). Two studies demonstrated the
presence of flavonoids in the brain tissue of mice (Abd El
Mohsen et al, 2002) and rats (Datla et al, 2001) after oral
administration. However, data on flavonoid concentrations
in human brains are not available.
Curcumin is a lipid-soluble compound that easily penetrates into the cytoplasm and accumulates in membranous
structures such as the plasma membrane, the endoplasmic
reticulum and the nuclear envelope (Jaruga et al, 1998). From
studies in mice, it became clear that curcumin is absorbed in
the intestine and subsequently metabolised. Biotransformation of curcumin takes place through reduction and
glucuronidation, and indeed traces of curcumin could be
found in the murine brain (Pan et al, 1999).
Supplementation with long-chain PUFAs can change
blood lipid and fatty acid profiles in healthy subjects
(Laidlaw & Holub, 2003). Brain bioavailability of PUFAs has
been studied extensively in rodents. The potential sources of
lipids in the nervous system are both in situ synthesis and
uptake from plasma. From studies in rat, it became clear that
the brain is clearly sensitive to alteration of dietary lipid
intake (Foot et al, 1982). Moreover, myelin formation in the
rat brain can be accelerated by dietary lipids (Salvati et al,
1996). Postnatal deficiency of essential fatty acids reduces
the mRNA levels of specific oligodendrocyte myelin proteins
in the mouse brain (DeWille & Farmer, 1992). These findings
support the rationale for supplementation with specific
PUFAs to support (re)myelination.
Conclusion
Research on the possible relationship between diet and MS is
important and several problems should be tackled. MS is the
most frequent neurodegenerative disease in young adults
and is currently diagnosed according to the McDonald
criteria (Dalton et al, 2002) by using magnetic resonance
imaging (MRI) evidence of dissemination of lesions in time
and space. MRI is an almost indispensable outcome measure
in clinical trials (Van Oosten et al, 2004) that makes clinical
research on the effect of dietary compounds complex and
expensive. Measuring PUFA and antioxidant levels in
different body compartments will be an important strategy
to select patients for complementary treatment. But it will
remain difficult to discriminate between abnormal physical
values present before the disease and those that are
secondary to the disease. Over the years, evidence has built
up on the impaired antioxidant status of MS patients and the
potential beneficial role of dietary antioxidant supplementation in reducing the severity and duration of attacks.
Deficiencies in PUFA levels have been observed in blood
and various other tissues of MS patients. Besides the
European Journal of Clinical Nutrition
immunosuppressive effects of PUFAs, their membrane
incorporation may also influence the function of cells within
the CNS. Moreover, there are accumulating data from
experimental models demonstrating the important role of
antioxidants and PUFAs on immunopathological mechanisms in MS. In our view, the present data warrant further
controlled clinical studies with antioxidants and PUFAs to
substantiate the relevance of these dietary compounds in the
treatment of MS.
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