In the absense of immunomodulation, earlier studies have concentrated on various simpler means to prevent the damage done to nervous tissue, preferably by means of added, possibly even previously reduced antioxidant substances. The critical question must now be raised, in how far such a therapy is at all in possession of reaching its target of action in nervous tissue (with or without an intact blood-brain barrier). On the other hand, the possibility of discovering an additive (basically cheap) therapy - also a challenge since no firm would sponsor any study - makes it worthwhile to look into the literature. I have performed various searches on glutathion and selenium, vitamins and (other) antioxidants, which are fused in the following review. Obviously, considerable overlapping occurs.
Warning: generally, all human amino-acids [AA]
are of the levo-type (while, e.g. snake poisons are right-turning
stereoisomers). Commercial AA may be a mixture of both and thus even toxic
for humans.
Oxidative Stress in MS
In a number of acute vascular diseases and events, and
in particular following cardiac arrest, it has been noticed that damage,
it has been noticed that cellular damage occurs with a free interval after
perfusion has been resumed. This can be related to the excess production
of peroxides (superoxide) in macrophages and leucocytes in respond to,
among others, production of nitric acid (NO). It should not be forgotten
that these cells utilize peroxides in their physiological defense against
infection. However, in these cases, a potent weapon is turned against the
hosts own cells. So far, no treatment has reached clinical use for the
purpose of reducing this damaging activity, but many drugs used demonstrate
some activity of the kind, occasionally resulting in an increase in infectious
complications.
Also in many chronic diseases, adverse
effects of oxidative stress may be of importance. Nordman et al.
[34] reported that chronic ethanol administration elicited an enhancement
in mitochondrial lipid peroxidation and a decrease in the glutathione level
in various extrahepatic organs, including brain and heart Vitamin A supplementation
attenuated the changes. Zigorsky et al. [35] found that the activity
of superoxide dismutase (a physiological excisting enzyme having the purpose
to reduce peripheral peroxide levels) in the erythrocytes of multiple sclerosis
patients was reduced, suggesting a lower enzymatic defense mechanisms against
oxidative stress. In accordance with other authors, Calabrese et al.
[36] found the activity of GSH reductase significantly increased in human
cerebrospinal fluid of MS patients, about twice the control values, whereas
the activity of glutathione peroxidase was markedly decreased as compared
to control values. At least, the activity of antioxidant enzymes is modified,
indicating the conceivable possibility of a pathogenic role of oxidative
stress in the determinism of the disease. Using another measure, Toshniwal
and Zarling [37] found that patients with acute exacerbation of MS had
significantly higher concentrations of pentane, which is released during
lipid peroxidation. Recently, v. d. Goes et al. [38] demonstrated
that reactive oxygen species appear to play a regulatory role in the phagocytosis
of myelin.
Even if demyelinization involves oxidative
mechanisms in the macrophages involved, this does not imply that a treatment
of MS can be seen in that direction. It is, however, most plausible that
high-dose steroids (with a proven antioxidant effect) do indeed act by
that mechanism in relapses of MS, but due to complications associated with
a prolonged use, the duration of such a therapy is limited. Indeed, Glabinski
et
al. [39] found that superoxide radical generation was lower in MS patients
given prednisone than in untreated patients, but was still above the level
of peroxide generation in controls. The current review considers other
approaches.
Glutathion and Selenium:
The AA Glutathione [GSH] forms together with selenium
two enzymes, glutathione peroxidase and glutathione reductase, both essential
to reduce the impact of oxidant destruction of cells. GSH itself cannot
just be added but must be synthetized intracellularly from glutamine, cysteine
and glycine (relation: Glutamic acid 1,47 : Cysteine 1,21 : Glycin 0,75,
see also comments on glutamate and cysteine below).
Finding a high prevalence of MS in
the same Finnish area in which also muscular dystrophy of the cattle had
accumulated, possibly due to nutritional lack of selenium and vitamin E,
Wikström et al. [1] speculated that a similar deficiency might
be involved also in MS-patients. They found the Selenium content of whole
blood was somewhat lower (av. 53 ng/ml) in MS patients as compared
to controls (69), and in both cases lower than international values. However,
the serum-values failed to confirm this tendency and also both vitamin
E and copper were found to be normal. In 1977, Shukla, Jensen and Clausen
[2] demonstrated a significant decrease in GSH peroxidase activity in erythrocytes
of patients with MS. Comparing the topographic differences in selenium
availability with the prevalence and death rates of MS in the USA, the
possibility of a relationship between low selenium content and high prevalence
of MS was suggested. Jensen
et al. [3] found both GSH peroxidase
and selenium levels decreased in both lymphocytes, granolycytes and erythrocytes
of MS patients as compared to normal controls whereas the activity of this
enzyme correlated to the selenium level [4] (unknown conclusion [5,6,7]).
In a later study [8], the Danish working group again demonstrated lowered
selenium values and lowered GSH peroxidase activities of major types of
haematogenous cells. In close agreement with these findings, haematogenous
cells in MS-patients showed increased peroxidation rates. A nonblinded,
biochemical dietary experiment on MS patients claimed that all abnormalities
could be normalized by daily intake of selenium, vitamin E, and vitamin
C. May et al. [9] administered 6 mg sodium selenite, 2 g vitamin
C, and 480 mg vitamin E a day for five weeks (Caution:
this dosage may be harmful when used for a longer time!) and
obtained a moderate (24%) increase of selen and a five-fold increase in
GSH peroxidase (which before the study had been lower than normal). Except
for testing the safety of this time-restricted treatment, a clinical effect
of it remains speculative. Measuring the concentration in plaques of MS-patients,
Langemann et al. [10] found GSH decreased while uric acid was increased.
The authors found that their results provided evidence for the involvement
of free radicals in MS. Also Szeinberg et al. [11] found a lower
activity of GSH peroxidase in erythrocytes but a normal activity in lymphocytes,
granulocytes and platelets of MS patients.
In contrast, Hunter et al.
[12] found that the activities of GSH peroxidase, and GSH reductase were
not significantly different from normal whereas that of uperoxide dismutase
was decreased in the erythrocytes from MS patients and d'Ilio et al.
[13] found none of these three enzymes reduced. Mazzella et al.
[14] found no difference in erythrocyte selenium whereas plasma levels
were even higher in MS-patients than in controls. Erythrocyte GSH peroxidase
activity was lower in MS whereas leucocyte levels did not demonstrate any
difference. In a twin study (14 subjects with definite MS where the 11
remaining co-twins had none), Korpela et al. [15] found no difference
in GSH peroxidase activity and selenium conentration, but the 3 patients
with progressive MS had a higher mean level of lipid peroxides. Measuring
the levels in cerebrospinal fluid [CSF], Calabrese et al.
[16] found the activity of GSH reductase increased, about twice the control
values, whereas the activity of GSH peroxidase was markedly decreased as
compared to control values. Jovicic et al. [17] found in the CSF
of MS-patients an increase of superoxide anion production, the elevation
of lipid peroxidation followed by the increase of superoxide dismutase
and GSH reductase activation. In an experimental study, Singh
et al.
[18] found that treatment of rat astrocytes with TNF-alpha or IL-1 resulted
in a decrease in intracellular GSH while pretreatment of astrocytes with
N-acetylcysteine, an antioxidant and efficient thiol source for GSH, prevented
cytokine-induced decrease in GSH and degradation of sphingomyelin.
Smith et al. [19] found no
difference in MS-patients with and without corticosteroid treatment and
controls concerning plasma selenium, zink and erythrocyte GSH peroxidase
concentration; then they found instead that erythrocyte copper concentration
was lower in MS because of steroid therapy. Disease acuity and disability
had no effect on trace-mineral status. In EAE, selen supplemtation had
no influence on neither survival, nor the erythrocyte activity [20].
Warren [21] hypothesized that the
feeding of newborn infants over a period of approx. 6 months on diets containing
insufficient vitamin A or selenium and to a lesser extent the vitamin E
necessary to safeguard vitamin A against peroxidative degradation is a
necessary condition but not a sufficient condition for the possible onset
of the disease later in life. In the same journal Foster [22] hypothesized
that thyroid hormone metabolism may also occur following selenium depletion.
Vitamins and other amino acids:
Note: Vitamins E, C and A, and GSH have already been mentioned
above while Vitamin D is described under environmental
factors. The controversy continues concerning Vitamin C intake:
a recent case-control study [32], generally supported a protective role
for components (Vitamin C and others) commonly found in plants (fruit/vegetables
and grains). However, Zhang et al. [33] found no associations between
intakes of fruits and vegetables and risk of MS. Use of vitamin C, vitamin
E, and multivitamin supplements was also unrelated to risk of MS. Apart
from this controversy, ascorbic acid acidifies the urine, thus helping
to control urinary infections.
Vitamin B12
has a suspected role in MS and has particularly a decreased level in patients
with an earlier start of the disease [23]. A possible association with
(again the just possible) association of MS among anaesthetists could be
their chronical exposition to nitrous oxide, again acting deleterious upon
Vit-B12 deposits. This effect must, however,
be considered purely speculative. Moreover, Vit-B12
does not reverse the associated macrocytic anemia, nor are the neurological
deficits of MS improved following supplementation with Vit-B12.
Concerning the sources of GSH, Cysteine
can be obtained from N-acetylcysteine which in itself has antioxidant
effects. Glutamate is, however, also a neurotransmitter, and hints have
been made that stimulation of glutamate signaling may be detrimental to
oligodendrocytes and may be involved in the pathogenesis of MS [24]. Measuring
the concentration of glutamate in CSF, Launes et al. [25] found
several times higher values in encephalitis and stroke, but not in MS comparet
to controls; also Klivenyi et al. [26] found normal values of glutamate
and aspartate in CSF of MS-patients. Contrary to this, Stover et al.
[27] found the levels of glutamate and aspartate in CSF doubled during
acute MS (are the diverging results connected to the word "acute?).
Starck et al. [28] found memantine, a glutamate antagonist, useful
in the treatment of nystagmus in MS.
Other scavengers of oxidative degeneration:
Uric acid, the naturally occurring product of purine
metabolism, may in itself cause symptoms when increased (e.g. hyperuricemic
gout). Recently, uric acid has been demonstrated to be s a scavenger of
oxidative radicals. A recent hungarian study [29] has shown that patients
with MS had lower levels of serum uric acid than the controls. Conversely,
statistical evaluation of the incidence of MS and hyperuricemic gout revealed,
that the hyperuricemia may protect against MS. Finally, uric acid was successfully
used to treat EAE in mice (see: Studies on MS).
Where does all this lead? A particular problem remains that the same substance can be depleted (possibly causally involved in the disease) and again increased as part of the (still insufficient) response to disease processes. Even if oxidant damage may be involved - and there is good evidence that this may be the case in MS, there is currently no proof that oxidant scavenging (= antioxidant therapy) offers any help. Conversely, in comparison with the research that has been done for newer substances, very little has been done to provide any confirmation for this, from MS-patients readily accepted therapeutical aspect; when compared with patients with other chronic diseases, the use of alternative treatments by MS patients is high [30,31].
Acknowledgement:
Thanks to Dr. Olav Axelson, Linköping, for important support.
Literature: