Rolf.Busch at t-online.de
Tue Oct 14 22:19:08 EST 1997
There is a lot of research going on in demyelinating diseases,
which inthe long run may be successful. But do we have to wait
passively? Is there nothing we can do now, immediately?
Are there any substances AVAILABLE NOW, which do
stimulate remyelination in demyelinating diseases?
I did a literature research, and I found quite a number of
substances, which might possibly stimulate remyelination
by different pathways. Theremay even be MORE of those
substances. On the other hand I realise, that a lot of this is
speculation, but speculation based on in vitro research,
based on animal research or based on extrapolation from
Here are my candidates (in no particular order):
-DHEA and/or progesterone;
-Insulin-like Growth Factor-1 (IGF-1) and other nerve growth
factors or substances, which stimulate the body's own
production of these factors;
-1,25-Dihydroxyvitamin D3 (vitamin D);
-retinoic acid (vitamin A);
-catalase and factors, which stimulate the production of this
enzyme (like NGF e.g.);
-combinations of NAC with progesterone, vitamin C, or
Trolox, a water-soluble vitamin E analogue;
-different free radical scavengers, vitamin E and idebenone;
-cysteine and cystine;
-electrical (magnetic) stimulation?
-polyunsaturated fatty acids;
-thiamin (vitamin B1)
I have compiled the following excerpts from medical articles, in
which I found these substances and their possible effect on
remyelination. And I should very much like to hear about
experience with these and other substances.
The restoration of MS patients to full health will ultimately be a
two step process. The first step being the development of an
effective treatment or cure for MS and the second the application
of therapeutic strategies designed to repair the existing damage
to myelin. ...this second step (is) known as remyelination.
Myelin is synthesised by a specialised cell in the CNS called an
oligodendrocyte. Oligodendrocytes develop from progenitor
(immature) cells that proliferate in a region of the brain called
the sub-ventricular zone.These progenitor cells migrate to the
regions of the brain that are to be myelinated, where they
differentiate (mature) into myelin producing oligodendrocytes.
Remyelination Promoted by Growth Factors
While the two growth factors mentioned above (FGF and PDGF)
do not stimulate mature oligodendrocytes to divide, FGF is
ableto increase the myelin forming potential of mature
oligodendrocytes even when tested on human cells. Similar
effects have been observed when using insulin-like growth
factor-1 (IGF-1). Growth factors such as PDGF, neurotrophin-3
and ciliary neurotrophic factor are able to increase the survival
of mature oligodendrocytes. Thus, the administration of these
growth factors to MS patients as therapeutic agents may protect
oligodendrocytes from destruction as well as promote
A number of strategies are currently being developed to promote
remyelination. The advances in the past few years have been
significant and offer tremendous hope. In the short term the
application of treatments that promote remyelination may slow
disease progression in MS patients and help prevent some of
the incapacitating symptoms. In the longer term,once an
effective treatment has been developed for MS, such
treatment may help MS patients regain function of those
deficits caused by this debilitating disease 1.
But regenerating myelin may also be beneficial
in demyelinating diseases for which no effective treatment has
been developed (e.g., multiple sclerosis). Indeed, the new myelin
may well be able to withstand new attack by the primary
demyelinating agent, either permanently or for long periods of
Immunoglobulins. The results of the immunoglobulin (IgG)
placebo-controlled trial conducted by Drs. Rodriguez and
Noseworthy at the Mayo Clinic will be available by year end.
Progesterone. Dr. Etienne Baulieu has recently shown that
progesterone stimulates remyelination in the rat PNS 2.
Another treatment showing promise is intravenous
immunoglobulin (IVIg) therapy. Animal studies have shown this
treatment may not only decrease exacerbations and neurological
disability, but may also hold the potential for myelin repair.
With respect to remyelination, different types of growth factors
are being tested with animal models. Human trials are expected
to begin in 1998 3.
(There is) evidence that growth factors may have a role in
promoting CNS remyelination by enhancing the survival and
stimulating the proliferation and recruitment of remyelinating
"Glial cell line-derived neurotrophic factor (GDNF) has
significant therapeutic potentials, in particular for
neurodegenerative disorders... our results indicate that 1,25-
(OH)2 D3 is effective at concentrations as low as 10(-10) M and
that retinoic acid has additive effects. These data indicate that
1,25-(OH)2 D3 is a potent inducer of GDNF expression and
suggest that 1,25-(OH)2 D3 may contribute to the regulation of
GDNF in vivo 5."
...this study indicates that clinically significant remyelination is
possible in human CNS 6.
The occurrence of remyelination depends upon the intensity and
time of exposition to the demyelinating agent. Remyelination in
the CNS with complete restoration of conduction may be
made by oligodendrocytes or Schwann cells which invade
the CNS when astrocytes are destroyed 7.
The limiting factor to remyelination is the persistence of the
Nevertheless the demonstration that the process occurs leads
to increasing hope that clinically useful remyelination may be
encouraged in the future either by more carefully controlling the
extent of demyelination or by finding ways of stimulating
oligodendrocyte proliferation and access to the axon 8.
...the use of immunosuppression, immunoglobulins, protein
growth factors, and glial cell transplantation are the primary
experimental therapies designed to promote CNS remyelination
Basic FGF and PDGF are known to stimulate their proliferation
and delay their differentiation. Lack or excess of retinoic acid
(RA) has been known for a long time to alter brain development
suggesting that this compound is involved in normal brain
development. Here we report that RA partially inhibits both
the proliferation and the differentiation of oligodendrocyte
precursor cells 10.
These findings indicate that IGF-I is a potent inducer of
brain growth and myelination in vivo.
Taken together, these in vivo studies indicate that IGF-I can
influence the development of most, if not all, brain regions, and
suggest that the cerebral cortex and cerebellum are especially
sensitive to IGF-I actions. IGF-I's growth-promoting in vivo
actions result from its capacity to increase neuron number,
at least in certain populations, and from its potent stimulation
of myelination 11.
The results indicate that brain development, particularly
myelination, was affected by a deficiency of vitamin B-6
prior to andincluding the period of rapid myelination 12.
NAC prevented the death of oligodendrocytes induced
NAC markedly enhanced the extent of spinal ganglion neuron
survival obtained with suboptimal concentrations of nerve
growth factor and of oligodendrocyte survival obtained with
suboptimal concentrations of CNTF or insulin-like growth
factor-1. Surprisingly, significant rescue of oligodendrocytes
from apoptosis was also observed with combinations of
NAC with progesterone, vitamin C, or Trolox, a
water-soluble vitamin E analogue, although not with any of
these compounds applied individually. These results
demonstrate that cocktails of small molecules such as those we
have studied may have beneficial effects not predictable from
the action of any individual member of the cocktail. In light of
the long clinical history of therapeutic use of NAC and the
other compounds identified in our studies, we suggest that it
may be of interest to examine use of NAC alone, or
combinations of NAC with the other small molecules we
have studied, in conditions in which certain toxin-mediated
forms of cell death or apoptosis contribute significantly to
Subsequent observations showed that the toxicity of glutamate
was mediated by free radical attack, the consequence of
glutathione depletion, apparently caused by the action of a
glutamate-cystine exchange mechanism that results in cystine
and thereby glutathione depletion. Thus, addition of cystine
or cysteine totally prevented the glutamate toxicity to
oligodendroglia. Second, glutamate exposure led to cystine
efflux. Third, glutathione levels decreased markedly in cells
exposed to glutamate, and this marked decrease preceded
the loss of cell viability. Fourth, glutamate toxicity could be
prevented totally by exposure to different free radical scavengers,
vitamin E and idebenone. The data thus show that glutamate is
highly toxic to oligodendroglia 14.
We show that myelination can be inhibited by blocking the action
potential of neighboring axons or enhanced by increasing their
electrical activity, clearly linking neuronal electrical activity to
Our findings indicate that IGFs play a crucial role in normal
oligodendrocyte development and myelination, and suggest
that IGFs may have applications for the promotion of
remyelination in myelin disorders such as MS 16.
These findings suggest that axonal electrical activity normally
controls the production and/or release of the growth factors
that are responsible for proliferation of oligodendrocyte
precursor cells 17.
These findings raise the possibility that IgG secreted in
demyelinating lesions might have the potential to promote
myelin repair 18.
These experiments suggest that immunoglobulins to a spinal cord
antigenmay induce proliferation of cells in the central nervous
system to promote remyelination 19.
These experiments support the concept that full CNS
remyelination is possible in human demyelinating diseases such
as MS. Manipulation of the immune response either by inhibiting
the function of T cells or by treatment with immunoglobulins
(possibly normal autoantibodies) appears to promote
remyelination. These experiments provide hope for patients
with fixed neurological deficits for whom there are currently no
available therapies 20.
These findings indicate that immunoglobulins reactive with
myelin autoantigens have the potential to promote myelin repair
Immunosuppression using cyclophosphamide or anti-T cell
monoclonal antibodies (mAbs) directed at CD4 or CD8
promoted remyelination of CNS axons in the spinal cords of
mice infected chronically with Theiler's virus... These findings
indicate that CNS remyelination occurs as a normal consequence
of primary myelin injury, but factors associated with immune T
cells somehow impair remyelination. Interference with the
function of immune T cells enhances CNS remyelination by
oligodendrocytes. Similar depletion of immune T cells may allow
for enhanced remyelination in the CNS of patients with chronic
multiple sclerosis 22.
This myelin repair is achieved by oligodendrocytes, which are
the myelinating cells of the central nervous system or by
oligodendrocytes precursors still present in adult central nervous
system. Several recently discovered growth factors can stimulate
oligodendrocytes precursors migration and proliferation, or act
as survival factors for mature oligodendrocytes. These glial
growth factors may represent a new therapeutic approach in
multiple sclerosis, aiming at the stimulation of the endogenous
capacities of remyelination 23.
...a diet deficient in vitamin E and a diet deficient both in vitamin
E and polyunsaturated fatty acids... Impaired myelin
formation was found in cases of both types of deficiency 24.
The oligodendrocytes were completely protected by catalase
from the cytotoxic effects of both oxygen radical generating
systems. However, superoxide dismutase, dimethylsulfoxide and
antioxidants such as vitamin E and glutathione did not protect
oligodendrocytes from the oxidant-mediated cytotoxicity. It
appears that hydrogen peroxide produced in these oxygen
radical-generating systems gives rise to toxic radicals that induce
the cell death of bovine oligodendrocytes in culture 25.
Recent studies have shown that the development
of oligodendrocytes, the myelin-forming cells of the CNS, is
extensively controlled by growth factors. These factors regulate
the proliferation, migration, differentiation, survival and
regeneration of oligodendroglial cells and the synthesis of myelin,
and often interact in a complex manner. Moreover, insulin-like
growth factor I (IGF-I) has proven effective for therapy of
experimental autoimmune encephalomyelitis (EAE) 25.
There are also prospects for increasing the remyelination which
occurs following acute inflammatory disease of the central
nervous system, through the combination of immunological
treatments that limit the disease process, growth factors that
recruit oligodendrocytes and implantation of glial progenitors
into demyelinated areas 27.
In the central nervous system, IGF-I promotes oligodendrocyte
directed myelination, and in central nervous sytem disorders,
such as multiple sclerosis, IGF-I promotes remyelination 28.
Dietary myo-inositol supplementation... increased
nodal remyelination, supporting a role of myo-inositol depletion
in the genesis of early diabetic neuropathy 29.
(-)Deprenyl increases the life span as well as activities of
superoxide dismutase and catalase 30.
Nerve growth factor, which induces catalase 31.
Maintenance on (-)deprenyl enhances selectively superoxide
dismutase (SOD) and catalase activity in the striatum 32.
(Antioxidants in general.) 33
Two weeks of arginine supplementation led to a significant
elevation of serum insulin-like growth factor concentrations 34.
A randomized placebo-controlled cross-over trial of nightly
oral DHEA administration (50 mg) of 6-month duration was
conducted. ...serum IGF-I levels increased significantly, and
IGFBP-1 decreased significantly for both genders, suggesting an
increased bioavailability of IGF-I to target tissues 35.
The importance of thiamin in treating Myasthenia Gravis and
Multiple Sclerosis cannot be over emphasized.
In the late thirties Stern, from Columbia University, was
employing thiamin hydrochloride intraspinally with astonishing
results in Multiple Sclerosis 36.
1 Research Directed Towards Understanding Remyelination -
Terrance Johns, PhD, Anthony Slavin, Claude Bernard, MSc,
PhD, Dsc, Professor of Neuroimmunology, La Trobe
University, Melbourne, Australia. (Website)
2 THE MYELIN PROJECT website: http://www.myelin.org/
3 RESEARCH UPDATE website. Summer, 1997. Written by
Susan Wells, MSAA. Reviewed by Herman J. Weinreb, M.D.,
NYU Medical Center
4 Histol Histopathol 1997 Apr;12(2):459-466
Growth factors and remyelination in the CNS.
Woodruff RH, Franklin RJ
Department of Clinical Veterinary Medicine, University of
5 Naveilhan P; Neveu I; Wion D; Brachet P: "1,25-
Dihydroxyvitamin D3, an inducer of glial cell line-derived
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Ghatak NR, Leshner RT, Price AC, Felton WL 3d
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Central nervous system remyelination clinical application of basic
Miller DJ, Asakura K, Rodriguez M
Department of Immunology, Mayo Clinic and Foundation,
Rochester, MN 55905, USA.
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Retinoic acid regulates the development of oligodendrocyte
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Laeng P, Decimo D, Pettmann B, Janet T, Labourdette G
Laboratory of Ontogenic Neurobiology, CNRS UPR 417,
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Carson MJ, Behringer RR, Brinster RL, McMorris FA
Wistar Institute, Philadelphia, Pennsylvania 19104.
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Effects of vitamin B-6 deficiency on the developing central
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Morre DM, Kirksey A, Das GD
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On the track of cell survival pharmaceuticals in the
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Noble M, Mayer-Proschel M
Ludwig Institute for Cancer Research, London, United Kingdom.
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Vulnerability of oligodendroglia to glutamate: pharmacology,
mechanisms, and prevention.
Oka A, Belliveau MJ, Rosenberg PA, Volpe JJ
Department of Neurology and Program in Neuroscience,
Children's Hospital, Boston, Massachusetts 02115.
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Induction of myelination in the central nervous system by
Demerens C, Stankoff B, Logak M, Anglade P, Allinquant B,
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Laboratoire de Neurobiologie Cellulaire, Moleculaire et Clinique,
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McMorris FA, Mozell RL, Carson MJ, Shinar Y, Meyer RD,
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Barres BA, Raff MC
Department of Biology, University College, London, UK.
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Immunoglobulins promote remyelination in the central nervous
Rodriguez M, Lennon VA
Department of Neurology, Mayo Clinic, Rochester, MN 55905.
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Immunoglobulins stimulate central nervous system remyelination:
electron microscopic and morphometric analysis of proliferating
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Immune promotion of central nervous system remyelination.
Rodriguez M, Miller DJ
Department of Neurology, Mayo Clinic, Rochester, MN 55905.
21 Neurology 1996 Feb;46(2):538-545
Immunoglobulins reactive with myelin basic protein promote
Rodriguez M, Miller DJ, Lennon VA
Department of Neurology, Mayo Medical School, Rochester,
MN 55905, USA.
22 Neurology 1992 Feb;42(2):348-357
Immunosuppression promotes CNS remyelination in chronic
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Rodriguez M, Lindsley MD
Department of Neurology, Mayo Medical School, Rochester,
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