MS and Antioxidants

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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].


Thanks to Dr. Olav Axelson, Linköping, for important support.


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  2. Shukla VK, Jensen GE, Clausen J. Erythrocyte glutathione perioxidase deficiency in multiple sclerosis. Acta Neurol Scand 1977;56:542-550.
  3. Jensen GE, Gissel-Nielsen G, Clausen J. Leucocyte glutathione peroxidase activity and selenium level in multiple sclerosis. J Neurol Sci 1980;48:61-7.
  4. Jensen GE, Clausen J. Glutathione peroxidase and reductase, glucose-6-phosphate dehydrogenase and catalase activities in multiple sclerosis. J Neurol Sci 1984;63:45-53.
  5. Jensen GE, Clausen J. Glutathione peroxidase activity, associated enzymes and substrates in blood cells from patients with multiple sclerosis - effects of antioxidant supplementation. Acta Pharmacol Toxicol 1986;59(Suppl 7):450-3.
  6. Polidoro G, Di Ilio C, Arduini A, La Rovere G, Federici G. Superoxide dismutase, reduced glutathione and TBA-reactive products in erythrocytes of patients with multiple sclerosis. Int J Biochem 1984;16:505-9.
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  8. Clausen J, Jensen GE, Nielsen SA. Selenium in chronic neurologic diseases. Multiple sclerosis and Batten's disease. Biological Trace Element Research 1988;15:179-203.
  9. Mai J, Sørensen PS, Hansen JC. High dose antioxidant supplementation to MS pattients. Effects on glutathion peroxidase, clinical safety, and absorption of selenium. Biological Trace Element Research 1990;24:109-17.
  10. Langemann H, Kabiersch A, Newcombe J. Measurement of low-molecular-weight antioxidants, uric acid, tyrosine and tryptophan in plaques and white matter from patients with multiple sclerosis. European Neurology 1992;32:248-52.
  11. Szeinberg A, Golan R, Ben-Ezzer J, Sarova-Pinhas I, Kindler D. Glutathione peroxidase activity in various types of blood cells in multiple sclerosis. Acta Neurol Scand 1981;63:67-75.
  12. Hunter MI, Lao MS, Burtles SS, Davidson DL. Erythrocyte antioxidant enzymes in multiple sclerosis and the effect of hyperbaric oxygen. Neurochem Res 1984;9:507-16.
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  16. Calabrese V, Raffaele R, Cosentino E, Rizza V. Changes in cerebrospinal fluid levels of malondialdehyde and glutathione reductase activity in multiple sclerosis. Int J Clin Pharmacol Res 1994;14:119-23.
  17. Jovicic A, Jovanovic M, Dordevic D, Magdic B, Dincic E, Malicevic Z.Oxidative and antioxidative activity in the patients with disseminated demyelinating disease of central nervous system. Vojnosanitetski Pregled 1997;54:193-202.
  18. Singh I, Pahan K, Khan M, Singh AK. Cytokine-mediated induction of ceramide production is redox-sensitive. Implications to proinflammatory cytokine-mediated apoptosis in demyelinating diseases. J Biol Chem 1998;273:20354-62.
  19. Smith DK, Feldman EB, Feldman DS. Trace element status in multiple sclerosis. Am J Clin Nutrition 1989;50:136-40.
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  21. Warren TR. Multiple sclerosis and infants fed on diets deficient in vitamin A or in selenium and vitamin E. Medical Hypotheses 1982;8:443-54.
  22. Foster HD. The iodine-selenium connection: its possible roles in intelligence, cretinism, sudden infant death syndrome, breast cancer and multiple sclerosis. Medical Hypotheses 1993;40:61-5.
  23. Sandyk R, Awerbuch GI. Vitamin B12 and its relationship to age of onset of multiple sclerosis. Int J Neurosci 1993;71:93-9.
  24. Matute C Characteristics of acute and chronic kainate excitotoxic damage to the optic nerve. Proc Natl Acad Sci USA 1998;95:10229-34
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  26. Klivenyi P, Kekesi K, Juhasz G, Vecsei L. Amino acid concentrations in cerebrospinal fluid of patients with multiple sclerosis. Acta Neurol Scand 1997;95:96-8.
  27. Stover JF, Pleines UE, Morganti-Kossmann MC, Kossmann T, Lowitzsch K, Kempski OS. Neurotransmitters in cerebrospinal fluid reflect pathological activity. Eur J Clin Invest 1997;27:1038-43.
  28. Starck M, Albrecht H, Pollmann W, Straube A, Dieterich M. Drug therapy for acquired pendular nystagmus in multiple sclerosis. J Neurol 1997;244:9-16.
  29. Staub M. A hugysav jelentp6ege az antioxidacios vedelemben [Uric acid as a scavenger in oxidative stress]. Orvosi Hetilap 1999;140:275-9.
  30. v d Ploeg HM, Molenaar MJ, v Tiggelen CW. Gebruik van alternatieve behandelwijzen door patienten met multipele sclerose [Use of alternative treatments by patients with multiple sclerosis. Ned Tijdschr Geneeskd 1994;138:296-9.
  31. Winterholler M, Erbguth F, Neundorfer B. [The use of alternative medicine by multiple sclerosis patients--patient characteristics and patterns of use]. [in German] Fortschr Neurol Psychiatrie 1997;65:555-61.
  32. Ghadirian P, Jain M, Ducic S, Shatenstein B, Morisset R. Nutritional factors in the aetiology of multiple sclerosis: a case-control study in Montreal, Canada. Int J Epidemiol 1998 Oct;27(5):845-852.
  33. Zhang SM, Hernan MA, Olek MJ, Spiegelman D, Willett WC, Ascherio A. Intakes of carotenoids, vitamin C, and vitamin E and MS risk among two large cohorts of women. Neurology 2001;57:75-80.
  34. Nordmann R, Ribiere C, Rouach H. Ethanol-induced lipid peroxidation and oxidative stress in extrahepatic tissues. Alcohol Alcohol 1990;25:231-7.
  35. Zagorski T, Dudek I, Berkan L, Mazurek M, Kedziora J, Chmielewski H. [Superoxide dismutase (SOD-1) activity in erythrocytes of patients with multiple sclerosis, article in Polish]. Neurol Neurochir Pol 1991;25:725-30.
  36. Calabrese V, Raffaele R, Cosentino E, Rizza V Changes in cerebrospinal fluid levels of malondialdehyde and glutathione reductase activity in multiple sclerosis. Int J Clin Pharmacol Res 1994;14:119-23.
  37. Toshniwal PK, Zarling EJ. Evidence for increased lipid peroxidation in multiple sclerosis. Neurochem Res 1992;17:205-7.
  38. van der Goes A, Brouwer J, Hoekstra K, Roos D, van den Berg TK, Dijkstra CD. Reactive oxygen species are required for the phagocytosis of myelin by macrophages. J Neuroimmunol 1998;92:67-75.
  39. Glabinski A, Tawsek NS, Bartosz G Increased generation of superoxide radicals in the blood of MS patients. Acta Neurol Scand 1993;88:174-7.
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Revised January 25, 2002