Multiple sclerosis (MS) is a
chronic inflammatory demyelinating disease of the central nervous
system (CNS) with partially known etiology. It is the most common cause
of neurological disability in young adults. Nutrition is commonly
accepted as one of the possible environmental factors involved in the
pathogenesis of MS. Omega‐3 polyunsaturated fatty acids (PUFAs) such as
eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are fatty
acids that possess several carbon–carbon double bonds. A diet
supplemented with PUFAs has clinical and biochemical effects in patients
with autoimmune diseases such as MS. Eicosapentaenoic acid and DHA are
found in high proportions in fish oil, and these molecules may have
anti‐inflammatory, antithrombotic, antioxidant, immunomodulatory
functions, and neuroprotective effects on the synaptogenesis and
biogenesis of the neuronal membrane. Oxidative stress (OS) that is
characterized by excessive production of reactive oxygen species and a
reduction in antioxidant defense mechanisms have been implicated in the
pathogenesis of MS. In consequence, a reduction in this phenomenon could
be beneficial for MS patients [1].
In this work, we describe the relationship of several oxidative stress
markers (glutathione redox system, mitochondrial ATPase activity, and
membrane fluidity) with the development of MS. Furthermore, we describe
the main findings of a clinical trial conducted with relapsing–remitting
MS patients who received a diet supplemented with 4 g/day of fish oil
or olive oil.
Pathologically, MS is characterized by
perivenous infiltration of lymphocytes and macrophages in the brain
parenchyma. There are four clinical manifestations of MS:
relapsing–remitting, primary progressive, secondary progressive, and
progressive‐relapsing. The MS lesions are typically scattered, and the
clinical picture can vary from a benign self‐limiting disorder to severe
and highly disabling disease. MS is a multifactorial disease involving
genetic, immunological, and environmental factors that trigger the
autoimmune process leading to the pathological changes of the disease.
In this regard, it has been proposed that a viral infection in which
self‐antigens that generate molecular mimicry with myelin proteins cause
a loss of tolerance against it, which results in the destruction of
myelin mediated by activated T lymphocytes in white matter of the brain
and sometimes extending into the gray matter, resulting in defects in
the conduction of nerve impulses that leads to symptoms, depending on
the affected site of the brain or spinal cord [1] (Figure 1).
According
to the areas of myelin destruction, sensory or motor symptoms are
affected (balance or vision disorders). The symptoms can change between
an “outbreak” or relapse (emergence of new neurological symptoms or
worsening of previous ones) and remission. Demyelinating lesions or
“plaques” of different sizes and locations are spread throughout the
CNS, and the onset of symptoms and response to treatment is unique to
each patient [2].
2. Oxidative stress and multiple sclerosis
OS
is a cellular state where the homeostasis of redox reactions is altered
when the production of reactive oxygen (ROS) and reactive nitrogen
species (RNS) exceed their elimination. These reactive species are
generated, among other causes, by oxidative metabolism. Neurons of the
CNS are very active in oxidative metabolism, as they are constantly
exposed to low‐to‐moderate levels of ROS, and these species are removed
by antioxidants (melatonin, vitamin D, vitamin E, glutathione) and
antioxidant enzymes (superoxide dismutase, catalase, glutathione
peroxidase, etc.). In chronic inflammatory diseases, such as MS,
antioxidant defenses are overcome, which leads to oxidative stress [3].
Collectively, the ROS are reactive species derived from oxygen that include the superoxide anion (O-), hydrogen peroxide (H2O2), and the hydroxyl radical (•OH). The RNS are reactive species derived from nitrogen and include nitric oxide (NO∙) and peroxynitrite (ONOO-).
The ROS and RNS are extremely unstable and reactive because they have
an unpaired electron in their outer orbital. They take electrons from
proteins, lipids, carbohydrates, and nucleic acids, causing damage to
biological membranes, genetic material, and other macromolecules. The
CNS is particularly vulnerable to oxidative damage since it has a very
active mitochondrial metabolism, which leads to high levels of
intracellular superoxide anions. Moreover, oligodendrocytes have low
levels of antioxidant enzymes and a high concentration of iron.
Unsaturated fatty acids are the most vulnerable to free radicals, and
because myelin has a high lipid‐to‐protein ratio, it is a preferred
target of ROS [4].
The ROS are generated by a number of cellular oxidative and metabolic
processes including activity of the enzymes of the mitochondrial
respiratory chain, xanthine oxidase, NADPH oxidase, monoamine oxidases,
and metabolism of arachidonic acid (AA) mediated by the activity of
lipoxygenases (LOX), and ROS are produced primarily by leakage of
electrons in the mitochondrial respiratory chain [3].
Numerous
studies in MS patients have shown an increase in the production of OS
markers (such as cholesteryl ester hydroperoxides) and lower levels of
uric acid (a ONOO- scavenger). These changes are accompanied
by significant deficiencies in antioxidant enzymes compared to healthy
subjects. The increase in ROS coupled with decreased antioxidant
capacity is not enough to entirely explain the pathogenesis of MS [4, 5].
Other reports suggest that the loss of myelin nerve sheath is possible
because the immune system participates in combination with defects in
the mitochondria, and these defects cause the generation of ROS and RNS.
Macrophages and monocytes release mediators of OS that degrade the
unsaturated fatty acids. The ROS have also been implicated as a mediator
of demyelination of axonal damage in MS and experimental autoimmune
encephalomyelitis (EAE) [6].
It is important to mention that in assessing platelets in MS patients,
increased activity of free radicals with decreased levels of important
antioxidants such as glutathione and alpha‐tocopherol has been reported [7] (Figure 2).
The
molecular mechanisms proposed to explain how ROS could specifically
mediate brain damage are the following: (1) The lower levels of
antioxidants can promote increased activity of lipoxygenase in CNS
stimulating leukotriene production, thereby increasing the
immunoinflammatory processes in the cerebral cortex; (2) the damage to
myelin can be caused by activation of T cells that may be activated for
the presence of free radicals produced by the synthesis route of AA.
Then appear the markers of OS associated with reduced activity of
superoxide dismutase and the increase in glutamine, followed by
increases of ∙OH and the production of peroxides which ultimately has a
negative impact on myelin. After that, the evident changes in
mitochondrial activity and finally changes in membrane fluidity
(particularly, mitochondrial membranes) appear [8].
Paraclinical
studies have shown an increased metabolism of the RNS in serum,
lymphocytes, and cerebrospinal fluid of MS patients, which correlate to
pathology studies. ONOO- is also closely associated with acute inflammatory lesions [9].
Damage to axons is mediated by the following: (1) failure in
mitochondrial energy metabolism due to inhibition of the respiratory
chain by nitric oxide, which in turn causes a decrease in Na+/K+ ATPase activity and alters Na+‐dependent
glutamate transporters, (2) over‐expression of glutamate receptors, (3)
oligodendroglial excitotoxicity, (4) massive influx of extracellular Ca++,
(5) activation of proteases, and (6) impaired axonal transport. These
mechanisms produce glutamate excitotoxicity and increased generation of
nitric oxide leading to nitrosative stress. Nitric oxide is a highly
toxic element that by itself blocks nerve conduction, especially in
demyelinated axons, and stimulates apoptosis. When nitric oxide is
combined with the superoxide anion, it generates a potent free radical,
the pro‐oxidant peroxynitrite. Glutamate in turn causes
neurodegeneration through the AMPA and NMDA receptors in
oligodendrocytes and astrocytes (Figure 3).
It is possible to explain the role of mediators using an experimental
model of autoimmune encephalitis: Protection against the experimental
disease occurs after administration of a glutamate antagonist [10].
Under
physiologic conditions, nitric oxide is produced from L‐arginine by
constitutive nitric oxide synthase (cNOS) and participates in a variety
of important biological functions such as immunoregulation of
inflammatory reactions, the downregulation of tumor necrosis factor
(TNF)‐α production, MHC II expression in macrophages, induction of
apoptosis in CD4 cells, physiological regulation of the mitochondrial
respiratory chain, inhibition of antigen presentation, and leukocyte
adhesion and migration. However, during inflammatory reactions, exposure
of macrophages to interferon (IFN)‐γ and TNF‐α results in the
activation of the inducible isoenzyme of NOS (iNOS), which increases up
to 10 times the levels of nitric oxide. Nitric oxide facilitates the
formation of peroxynitrite radicals. Only cells capable of generating a
high flow of NO• have the potential for causing nitrosative stress. The
role of nitric oxide in MS is therefore complex, and in fact,
peroxynitrite is definitely more toxic than nitric oxide [9] (Figure 4).
3. Reactive oxygen species, cytokines, and axonal damage in multiple sclerosis
Mechanisms
of axonal damage are the consequence of the presence of TNF‐α, matrix
metalloproteinases (MMPs), ROS, antibodies, increased glutamate, and
aspartate, and these molecules cause excitotoxicity in MS patients.
Glutamate is increased in MS patients (active lesions) especially in
white matter of normal appearance. Mature oligodendrocytes and
astrocytes are highly sensitive to glutamate due to the expression of
AMPA and NMDA receptors [9].
The myelin sheath can be damaged by cytokines, autoantibodies, ROS,
proteolytic enzymes, and phagocytosis. Increased ROS by activated
microglia (specialized macrophages of the CNS) during the immune
response gives a state of increased lipid peroxidation, and the
oligodendrocyte cell is the cell most susceptible to damage by ROS.
Myelin degradation may be the result of lipid peroxidation mediated by
peroxides, but the role of these specific toxic factors in the
pathogenesis of MS remains partially elusive [9].
4. Glutathione system and multiple sclerosis
In
a recent study, the oxidation of DNA in the nucleus of oligodendrocytes
and oxidation of lipids in the myelin of oligodendrocytes and axons
were observed. This oxidation was associated with the active process of
demyelination and neurodegeneration. Active lesions in
relapsing‐remitting MS (RRMS) and progressive course patients were
associated with inflammation, lipid peroxidation, and DNA oxidation [11]. Similarly, Ortiz et al. [12]
observed an increase in serum lipid peroxides and nitrite/nitrate
levels and the activity of glutathione peroxidase in patients with RRMS
compared to healthy individuals.
Reduced ubiquinone and
vitamin E levels, and reduced activity of the enzyme glutathione
peroxidase in lymphocytes and granulocytes were reported (with a
decrease in 51 and 78%, respectively), as well as a decrease in
glutathione reductase activity in granulocytes (27%) and lymphocytes
(8%) [13]. In contrast, in 2012, Tasset et al. [14]
found an increase in activity of the glutathione reductase in patients
with RRMS when compared to control subjects (1.3 ± 0.9 vs 0.3 ± 0.19,
P < 0.01), and an increased ratio of reduced glutathione to oxidized
glutathione (GSH/GSSG) in these patients (28.2 ± 39.6 vs 4.0 ± 2.9,
P < 0.01). Similarly, an increase was found in the levels of oxidized
glutathione and also increased concentrations of isoprostanes and
malondialdehyde (MDA) in patients with MS [15, 16].
4.1. Glutathione deficiency and multiple sclerosis
There
are several reports in the literature that relate the decrease or
alteration of glutathione (GSH) metabolism with several
neurodegenerative diseases. Biochemical analysis of postmortem brains
has provided evidence for the generation of oxidative stress during the
course of the disease since the total GSH content is reduced by 40–50%
compared to controls. Also in several brain regions, we have found
increased levels of lipid peroxidation [17].
The ratio GSH/GSSG (usually 10:1) is considered consistent with the
concept of oxidative stress as an important part in the pathogenesis of
MS. Moreover, low concentrations of GSH appear to be an important
indicator of oxidative stress during the progression of MS. Although the
decrease in GSH alone is not responsible for the degeneration of glial
cells and neurons, reduced GSH could increase the susceptibility to
other stressful factors and contribute to neuronal damage at glia and
neuron cells. Glutathione has been reported to protect mitochondrial
complex I activity against nitrosative stress, as S‐nitrosoglutathione
is formed. When this complex increases its content of nitrotyrosine and
nitrosothiol groups in response to nitrosative stress, its activity is
inhibited and therefore ATP production is diminished, which causes
neuronal degeneration [10].
The role of glial cells in generating ROS in MS and the selective
vulnerability of neurons is due to activated glial cells surrounding
these neurons, as these glial cells are also directly involved in GSH
levels. The engagement of the glutathione system in astroglial cells
contributes to the reduction in its antioxidant defenses and so poor
glial defense could contribute to existing neuronal damage (Figure 5) [10].
Furthermore, the specific activities of some enzymes that metabolize
GSH are high, as in the case of glutathione peroxidase, glutathione
reductase, and glutathione S‐transferase. Other products of OS are also
elevated, as in the case of 4‐hydroxynonenal (4‐HNE, a product of lipid
peroxidation of polyunsaturated omega‐6 fatty acids) [17].
A
new proposal is that a genetic defect of glutathione synthesis may be
the initial event in the failure of the antioxidant defenses. In
neurodegenerative diseases, a decreased GSH level is accompanied by
dysfunction of the mitochondrial complex I and complex IV and promotes
oxidative stress [18].
We found a significant decrease in GSH levels in the cerebrospinal
fluid of patients with this disease, and, in addition, proton magnetic
resonance studies have shown a 50% decrease in GSH levels in the frontal
cortex of patients with MS (Figure 5).
5. Mitochondria
Mitochondria
are granular and filamentous organelles found in the cytoplasm of all
eukaryotic cells and are the main site of adenosine triphosphate (ATP)
synthesis by the processes of oxidative phosphorylation. These
organelles vary in size and shape depending on the source and metabolic
status, but are often ellipsoids of about 5 microns in diameter and
1 micron long. A typical eukaryotic cell contains more than 2,000
mitochondria, which takes up about one‐fifth of the cell volume, an
amount that is needed to meet the energy demands of the cell. Its main
function is the mitochondrial respiration process in which the reducing
power produced in the oxidation reactions enters the electron transport
chain and energy is captured in the form of adenosine triphosphate
(ATP). Mammalian tissues containing more mitochondria are the heart and
brain [19].
The mitochondrion is formed by two membranes: the outer membrane and
the inner membrane, which is highly folded, and the inner matrix is gel
(approximately 50% water) [20].
The
outer mitochondrial membrane contains porin, a pore‐forming protein
that allows diffusion of up to 10 kD molecules). The inner membrane
contains approximately 75% protein and 25% lipids by weight, and it is
much richer in outer membrane proteins. The inner membrane is permeable
only to carbon dioxide (CO2), oxygen (O2), and water (H2O). The passage of metabolites such as ATP, adenosine diphosphate (ADP), pyruvate, calcium ions (Ca2+), and phosphate (PO4)
is regulated by controlling the transport proteins. This controlled
permeability allows the generation of ionic gradients and results in the
compartmentalization of metabolic functions between the cytoplasm and
mitochondria. The inner membrane components of the respiratory chain are
responsible for the synthesis of ATP (ATP synthase FoF1) [22],
where the enzyme complex is housed. The inner membrane is arranged in
ridges, giving it a large surface area: A single mitochondrion may have
more than 10,000 sets of electron transfer systems (respiratory chain)
and ATP synthase molecules distributed throughout the membrane's
internal surface [21].
The inner membrane is, from the functional point of view, the most
important because it contains the components of the respiratory chain
and proteins necessary for the synthesis of ATP [21].
The mitochondrial matrix is the space delimited by the inner membrane
and contains the pyruvate dehydrogenase complex and the enzymes of the
tricarboxylic acid cycle (TCA), the fatty acid oxidation, and the
oxidation of amino acids [21] (Figure 6).
The
chemical energy required for cellular activities such as biosynthesis,
transportation of ions and molecules, and mechanical work comes from
ATP. Mitochondria generate more than 90% of the energy needed for the
proper functioning of tissues that are highly dependent on aerobic
metabolism, such as the brain and heart. This subcellular organelle
provides the energy necessary for the production of ATP [22].
Depending on cell type and metabolic state, mitochondria consume
approximately 90–95% of the oxygen consumed by the cell. The energy of
this process, in which electrons are transferred from the substrates of
the TCA to oxygen, is coupled to vectorial transport of H+ from the mitochondrial matrix space [22].
The electron carriers, reduced nicotinamide dinucleotide adenine (NADH) and reduced flavin dinucleotide adenine (FADH2),
originating mainly in the TCA cycle, confer the energy that electrons
carry. This energy is released gradually along the respiratory chain in
the mitochondrial inner membrane. In this membrane, an exchange of
electrons between the enzymatic complexes is given by NADH or FADH2 [20].
The
complexes are as follows: I (NADH‐ubiquinone reductase), II
(succinate‐ubiquinone reductase), III (ubiquinol‐cytochrome c
reductase), IV (cytochrome oxidase), and V (ATP synthase complex FoF1) [20].
Electron transport is carried out by complexes I, III, and IV that
produce a flow of electrons accompanied by a movement of protons from
the mitochondrial matrix to the intermembrane space (space between the
inner and outer mitochondrial membrane). This produces a difference in
proton concentration and a difference in charge across the membrane [20]. The proton‐motive force generated thereby drives protons through the F0F1‐ATP synthase, allowing condensation of a phosphate group to ADP, with the formation of ATP [23]. Meanwhile, the complex F0F1‐ATP
synthase is an enzyme located in the inner membrane of the
mitochondria, responsible for ATP synthesis from ADP and a phosphate
group (Pi), and the energy is supplied by a flow of protons (H+).
The difference between the terms ATPase and ATP synthase is that the
enzyme has a dual function: It breaks down ATP to ADP and Pi (activated
ATPase), and it also allows for catalyzing Pi binding of ADP using the
proton gradient for ATP synthesis (ATP synthase activity). As complex V
has both functions, we can name it indiscriminately when speaking in
general terms of the enzyme [23]. This enzyme is constituted by two components: a soluble portion (F1), located in aqueous medium, and another portion (Fo), which is lipid soluble. The Fo part is inserted into the lipid bilayer and is sensitive to the antibiotic oligomycin (Figure 7).
On
the other hand, pathophysiological features exhibited the association
between mitochondrial dysfunction, decreased activity of complex I and
complex IV of the electron transport chain, and the glutathione system
in MS [23].
6. Mitochondria and multiple sclerosis
In
acute phases of the disease, axonal degeneration correlates with the
severity of inflammation. This type of injury has been used in an
experimental model of autoimmune encephalomyelitis (EAE), where acute
mitochondrial damage within axons is detected and later suffers from
focal damage as a preliminary pathological step of axonal damage [15].
Complex IV of the mitochondrial electron transport chain has a binding site for O2 (The final acceptor in the respiratory chain) and catalyzes the reduction in O2 to H2O.
Interestingly, nitric oxide inhibits mitochondrial respiration by
reacting with either the reduced or the oxidized binuclear site of
cytochrome c oxidase, leading to ATP depletion. In cases of excessive
nitric oxide production, complete inhibition of cytochrome c oxidase has
been shown to contribute to pathology.
At the same time, interrupting the
electron transport chain by binding of NO to complex IV increases
electron release, thus facilitating the formation of reactive oxygen
species, firstly superoxide anion and subsequently H2O2 and OH..Peroxynitrite
has a direct effect on mitochondria leading to lipid peroxidation of
membrane lipids and thus damaging the complexes of the respiratory chain
and mitochondrial DNA. Opening of permeability transition pores and
release of cytochrome C from mitochondria initiate apoptosis (Figure 8).
At
the stage of acute inflammation, a set of mechanisms that alter
mitochondrial function is produced. The energy deficit causes structural
and functional damage to macromolecules by increased ROS that
ultimately leads to severe axonal damage. In these events, the
mitochondria has an important role; therefore, if we know what the
mechanisms involved in glial and neuronal alterations are, we must be
able to identify the elements that can be used as effector elements and
design drugs to control and reduced harm during the stage of relapse [14].
Many
demyelinated axons survive during a relapse, and these can become
chronically demyelinated axons, in which case axonal mitochondria
develop compensatory mechanisms to cope with the lack of myelin. There
are reports in which inactive lesions from chronic demyelinated axons of
patients with MS are observed. In such reports, they have found an
increase in the activity of mitochondrial complex IV and increased
synphilin anchoring protein [19]. However, axons progressively degenerate in chronic lesions of MS patients. In the absence of myelin, redistribution of Na+
occurs to maintain the transmission of nerve impulses that increases
energy demand, and this produces a situation of “virtual hypoxia.” At
the end, the demand exceeds the capacity of axonal mitochondria to
produce enough ATP, which causes an increase in the concentration of Ca2+ in the axon. Ca2+
pumping and extended levels of intramitochondrial calcium leads to
opening pores, rupture of the outer mitochondrial membrane, and release
of cytochrome C, finally leading to apoptosis (Figure 8).
One
of the questions we have not answered is: Why are mitochondria helpless
and overwhelmed by the energy demand and how does this happen? Are the
axons unable to maintain stable mitochondrial activity in
demyelination?. This reflects the inability of the cell to carry and
generate mitochondria. Dutta et al. [23]
have shown decreased gene expression of 26 nuclear‐encoded subunits of
the oxidative phosphorylation chain in non‐demyelinated motor cortex
from MS patients, which coincided with a significant reduction in
activity of NADH dehydrogenase and ubiquinol‐cytochrome c reductase . In
the progressive phase of MS, it is postulated that chronically
demyelinated axons are unable to maintain mitochondrial function, and
thus, a deficit of ATP synthesis coupled with oxidative stress results
in irreversible axonal damage.
7. Effect of fish oil (Omega3) and olive oil on membrane fluidity, ATPase activity in relapsing‐remitting multiple sclerosis.
The mechanism of action for omega‐3 PUFAs is suggested to be attributed to immunomodulation and antioxidant action [24].
For instance, omega‐3 PUFAs decrease the production of inflammatory
mediators (eicosanoids, cytokines, and ROS) and the expression of
adhesion molecules. They both act directly by replacing AA as an
eicosanoid substrate and inhibiting AA metabolism and indirectly by
altering the expression of inflammatory genes through effects on
transcription factor activation. Omega‐3 PUFAs also give rise to
anti‐inflammatory mediators (resolvins and protectins) [25].
Effects of resolvins and protectins include reducing neutrophil
trafficking, cytokine, and ROS regulation and lowering the magnitude of
the inflammatory response [26].
Previously,
we developed a twelve‐month randomized double‐blind controlled clinical
trial in 50 patients with relapsing‐remitting MS. Patients received an
oral dose of 4 g/day of fish oil (containing a total of 800 mg of EPA
and 1600 mg of DHA) or olive oil. Fasting blood samples were collected
at baseline and after 6 and 12 months of the trial, in order to evaluate
the effect of consumption of omega‐3 PUFAs on some markers of oxidative
stress at the peripheral level. The initial findings of this work were
the decrease in serum levels of TNFα, IL‐1β, IL‐6, and nitric oxide
metabolites compared with the placebo group [27].
On
the other hand, after 12 months of intervention, supplementation with
omega‐3 PUFAs significantly enhanced the quantities of serum omega‐3
highly unsaturated fatty acids compared with baseline values.
Additionally, the levels of medium‐chain monounsaturated fatty acids
were significantly decreased. The olive oil supplementation induced
minor decreases in EPA and DHA levels after 12 months of intervention.
There were significant increases in both EPA and DHA in the group given
fish oil supplementation compared to the control group receiving olive
oil. These increases were associated with a concomitant decrease in AA.
Consequently, the omega‐3 fatty acid index in the fish oil group
increased significantly, and the ratios of n‐6/n‐3 and AA/EPA were
decreased [28].
No
differences in glutathione reductase activity and content of reduced
glutathione, oxidized glutathione, and oxidized/reduced glutathione
ratio were seen after 12 months of supplementation with omega‐3 PUFAs.
However, a trend in favor of omega‐3 PUFAs supplementation was observed
in GSSG levels and glutathione reductase activity at 12 months of
intervention between the study groups [28].
A
steady decrease in mitochondrial ATPase activity in platelets was
observed in the groups given omega‐3 fatty acid and the control group
receiving olive oil. Membrane fluidity of platelets was significantly
reduced in MS patients. Interestingly, a significant increase in
platelet membrane fluidity was observed in the groups receiving omega‐3
fatty acid and the control group receiving olive oil. As well, the
fluidity of erythrocyte membranes was unchanged for both treatments
(Unpublished results).
Epidemiological and experimental
studies suggest an increased incidence of MS in populations with a high
intake of saturated fats mainly from animal sources. Therefore, by
consuming a diet high in fatty acids, without an appropriate number of
unsaturates, a shift is produced in the integrity and functionality of
the membrane [29].
An optimal balance in the consumption of fatty acids includes 35%
polyunsaturated fatty acids and 65% saturated fatty acids, and the
appropriate proportion of PUFA to maintain membrane balance is 50%
omega‐3 with 50% omega‐6. The above ratio was a factor that inactivated
the CD4 autoreactive cells in the CNS, a phenomenon that prevents the
production of proinflammatory cytokines and free radicals [30].
Membrane
fluidity depends on the temperature, the ratio of saturated/PUFA fatty
acids, the presence of “lipid rafts,” and the proportion of cholesterol
present at the membrane [31].
Previous studies in patients with rheumatoid arthritis had increased
cell membrane rigidity compared to membranes from those receiving
immunomodulatory treatment. Our results showed diminished platelet
membrane fluidity in MS patients and that proper membrane fluidity is
restored with treatment of omega3 PUFAs. The increase in platelet
membrane fluidity is directly related to the incorporation of PUFA‘s.
Furthermore, the increase in membrane fluidity is accompanied with a
significant decrease in mitochondrial ATPase activity. This ensures that
the activity of ATP synthesis in mitochondria remains elevated.
8. Conclusions
The
inflammatory process seen in MS is due to an excess production of
pro‐inflammatory cytokines, which leads to increased secretion of ROS.
Oxidative stress plays a preponderant, key role in the pathogenesis of
MS. Reactive oxygen species generated by macrophages have been
implicated as mediators of demyelination and axonal damage in EAE and
MS. The main findings of a clinical trial conducted with
relapsing‐remitting MS patients who received a diet supplemented with
4 g/day of fish oil or olive oil are the following:
- Fish oil supplementation resulted in a high increase in proportions of EPA and DHA, leading to a decrease in AA concentrations as well as the AA/EPA ratio. These changes in fatty acids are indicative of a reduction in the production of inflammatory eicosanoids from AA and an increase in anti‐inflammatory mediators such as resolvins and protectins.
- No differences in glutathione reductase activity, content of reduced and oxidized glutathione, and GSH/GSSG ratio were seen after 12 months of supplementation. However, fish oil supplementation resulted in a smaller increase in GR compared with the control group. In addition, there was a significant change in glutathione reductase activity within subjects in the fish oil group after 6 months of treatment, while no significant differences within subjects were observed in the control group, suggesting a possible effect of fish oil on antioxidant defense mechanisms of the cell. Although glutathione reductase activity was not significantly different between the groups, fish oil supplementation resulted in a smaller increase in GR compared with the control group, suggesting a possible antioxidant effect of fish oil supplementation.
- Membrane fluidity of platelets was significantly reduced in MS patients. That membrane property steadily increased in the groups given omega‐3 fatty acid and the control group receiving olive oil. The increases in membrane fluidity of platelets were associated with a decrease in mitochondrial ATPase. As well, the fluidity of erythrocyte membranes was unchanged for both treatments (unpublished results).Oxidative stress (OS) as a biomarker for multiple sclerosis (MS) and disease progression is the subject of studies being conducted around the world.
These studies are showing success at stopping and reversing the damage done by the demyelination caused by OS.
Known for years as an instigator of inflammation, OS is also considered to be neurodegenerative. Recent observations confirm the fact that OS is also an important factor associated with demyelination in MS.
OS is caused by an imbalance in free radicals that damage the nucleic acids, proteins, and lipids in the body. This is what creates inflammation. The byproduct of this action creates markers for OS.
Read more: ‘Magnet therapy’ may be effective in treating MS symptoms »
The role of stress in MS
OS markers can be used to determine the progression of MS.
These markers are also showing success as predictors of high disability in MS, helping direct the course of treatments recommended by medical professionals.
Chronic inflammation causes damage to the central nervous system and is attributed to MS. By calming this activity, researchers believe they have the ability to slow down disease progression.
Understanding the role of OS in MS appears to be vital.
Multiple sclerosis is generally divided into three types: Relapsing-remitting (RRMS), secondary progressive (SPMS), and primary progressive (PPMS).
The recent studies are showing that inflammation is the key instigator for relapses in RRMS, while permanent nerve damage is the root of PPMS and SPMS.
Read more: Marijuana touted as treatment for multiple sclerosis »
Activating a pathway
This nerve damage was thought to be permanent, but studies are now showing that OS can be halted by activating the Nrf2 pathway in the human body.
The Nrf2 pathway is a powerful protein found in every cell throughout the body. It regulates the antioxidant stress defense.
By activating it, researchers say that remyelination can occur. When remyelination occurs, the progression and disability from MS can be slowed down or even reversed.
Looking at OS at each stage of MS is a key element in understanding how the disease progresses.
OS markers can predict high disability in MS and are associated with different aspects of disease progression.New disease modifying drugs designed to treat MS target OS pathways.
Researchers say that activating one’s own self-defense mechanisms such as the Nrf2 pathway, the body can fight free radicals and slow down the damage caused by MS.
When Nrf2 is activated, it produces antioxidant enzymes such as catalase, glutathione, and superoxide dismutase (SOD). These antioxidant enzymes are powerful enough to neutralize many free radicals. Studies show that activated Nrf2 successfully slowed down the rate of demyelination.
Read more: The effects of coffee and alcohol on multiple sclerosis »
The role of antioxidants
Antioxidants such as vitamin C, vitamin E, berries, and juices have typically been used to neutralize free radicals and prevent the damage they cause.
One molecule of antioxidants from these sources neutralizes one free radical. However, there is a tipping point where the antioxidants are inadequate to take care of the damage, and additional help is needed.
Myricetin is an antioxidant shown to mitigate demyelination. Plants such as Barleria lupulina are showing benefits to the Nrf2 pathway and warrant further research on their effects on MS and other neurodegenerative diseases.
It was also reported that melatonin —10 milligrams daily for 30 days — caused a statistically significant increase in antioxidative enzymes, benefitting the Nrf2 pathways.
While research shows therapeutic potential lies in antioxidants, using OS markers as biomarkers of MS severity or relapse could be a helpful diagnostic tool.
And due to their ability to reduce OS, adding antioxidants to immunotherapy may be beneficial for people with MS.Continued research on OS, antioxidants, and the Nrf2 pathway could provide more solutions for people with MS.
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