Stimulating remyelination

[Rolf Busch]

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
related research.

Here are my candidates (in no particular order):

-immunoglobulins;
-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.);
-vitamin B6;
-NAC;
-combinations of NAC with progesterone, vitamin C, or 
Trolox,   a water-soluble vitamin E analogue; 
-different free radical scavengers, vitamin E and idebenone;
-arginine;
-myo-inositol;
-cysteine and cystine;
-antioxidants;
-electrical (magnetic) stimulation?
-cyclophosphamide;
-polyunsaturated fatty acids;
-deprenyl
-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.

Rolf Busch
(Hamburg/Germany)

---------------------------------------------------------------
 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
 remyelination. 

Conclusion

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
time.

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 
oligodendrocytes 4.

"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 
demyelinating agent.

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
9.

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 
by glutamate. 

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 
disease 13.

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 
myelinogenesis 15.

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
21.

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.

REFERENCES:

1 Research Directed Towards Understanding Remyelination - 
An Overview.
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
Cambridge, UK.

5 Naveilhan P; Neveu I; Wion D; Brachet P: "1,25-
Dihydroxyvitamin D3, an inducer of glial cell line-derived
neurotrophic factor."
NEUROREPORT, 7 (13) 2171-5  /1996 Sep 2
Institut National de la Sante et la Recherche Medicale, Centre
Hospitalier Universitaire, Angers, France.

6 J Neuropathol Exp Neurol 1989 Sep;48(5):507-518
Remyelination in the human central nervous system.
Ghatak NR, Leshner RT, Price AC, Felton WL 3d
Department of Pathology (Neuropathology), Medical College of
Virginia, Virginia Commonwealth University, Richmond 23298.

7 Arq Neuropsiquiatr 1988 Sep;46(3):292-297
Myelination, demyelination and re-myelination in the central
nervous system.

8  Adv Neurol 1988;47:215-254
Remyelination in the central nervous system and the peripheral
nervous system. 
Ludwin SK

9 Brain Pathol 1996 Jul;6(3):331-344
Central nervous system remyelination clinical application of basic
neuroscience principles.
Miller DJ, Asakura K, Rodriguez M
Department of Immunology, Mayo Clinic and Foundation, 
Rochester, MN 55905, USA.

10 J Neurosci Res 1994 Dec 15;39(6):613-633
Retinoic acid regulates the development of oligodendrocyte
precursor cells in vitro. 
Laeng P, Decimo D, Pettmann B, Janet T, Labourdette G
Laboratory of Ontogenic Neurobiology, CNRS UPR 417, 
Strasbourg, France.

11 Neuron 1993 Apr;10(4):729-740
Insulin-like growth factor I increases brain growth and central
nervous system myelination in transgenic mice.
Carson MJ, Behringer RR, Brinster RL, McMorris FA
Wistar Institute, Philadelphia, Pennsylvania 19104.

12 J Nutr 1978 Aug;108(8):1260-1265
Effects of vitamin B-6 deficiency on the developing central
nervous system of the rat. Myelination.
Morre DM, Kirksey A, Das GD

13 Perspect Dev Neurobiol 1996;3(2):121-131
On the track of cell survival pharmaceuticals in the
oligodendrocyte type-2 astrocyte lineage. 
Noble M, Mayer-Proschel M
Ludwig Institute for Cancer Research, London, United Kingdom.

14 J Neurosci 1993 Apr;13(4):1441-1453
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.

15 Proc Natl Acad Sci U S A 1996 Sep 3;93(18):9887-9892
Induction of myelination in the central nervous system by
electrical activity.
Demerens C, Stankoff B, Logak M, Anglade P, Allinquant B,
Couraud F, Zalc B, Lubetzki C
Laboratoire de Neurobiologie Cellulaire, Moleculaire et Clinique,
Institut National de la Sante et de la Recherche Medicale, Unite
134, Hopital de la Salpetriere, Universite Pierre et Marie Curie,
Paris, France.

16 Ann N Y Acad Sci 1993 Aug 27;692:321-334
Regulation of oligodendrocyte development and central nervous
system myelination by insulin-like growth factors.
McMorris FA, Mozell RL, Carson MJ, Shinar Y, Meyer RD,
Marchetti N
Wistar Institute, Philadelphia, Pennsylvania 19104-4268.

17 Nature 1993 Jan 21;361(6409):258-260
Proliferation of oligodendrocyte precursor cells depends on
electrical activity in axons. 
Barres BA, Raff MC
Department of Biology, University College, London, UK.

18 Ann Neurol 1990 Jan;27(1):12-17
Immunoglobulins promote remyelination in the central nervous
system.
Rodriguez M, Lennon VA
Department of Neurology, Mayo Clinic, Rochester, MN 55905.

19 Lab Invest 1991 Mar;64(3):358-370
Immunoglobulins stimulate central nervous system remyelination:
electron microscopic and morphometric analysis of proliferating
cells.
Rodriguez M
Department of Neurology, Mayo Clinic, Rochester, Minnesota.

20 Prog Brain Res 1994;103:343-355
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
CNS remyelination.
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
virus-induced demyelinating disease.
Rodriguez M, Lindsley MD
Department of Neurology, Mayo Medical School, Rochester,
MN.

23 Presse Med 1994 Nov 5;23(34):1577-1581
Multiple sclerosis: role of growth factors and remyelination.
Lubetzki C
INSERM U-134, Hopital de la Salpetriere, Paris.

24 Nutr Metab 1976;20(2):95-111
The influence of vitamin E deficiency and combined deficiency in
vitamin E and polyunsaturated fatty acids on the biosynthesis and
degradation of rat central nervous system myelin.
Dinesen B, Clausen J

25  J Neurosci Res 1991 May;29(1):100-106
Oligodendroglial cell death induced by oxygen radicals and its
protection by catalase.
Kim YS, Kim SU
Department of Medicine, University of British Columbia,
Vancouver, Canada.

26 Brain Pathol 1996 Jul;6(3):313-329
Regulation of oligodendrocyte development and CNS
myelination  by growth factors: prospects for therapy of
demyelinating disease.
McMorris FA, McKinnon RD
Wistar Institute, Philadelphia PA 19104-4268, USA.

27 AU: Compston A
TI: Brain repair.
SO: JOURNAL OF INTERNAL MEDICINE, 237 (2) 127-34
 /1995 Feb/ 
CS: University of Cambridge Neurology Unit, Addenbrooke's 
Hospital, UK.

28 Insulin-Like Growth Factor (IGF-I) Induces Myelination of
Peripheral Sensory Neurons
James W. Russell, Hsin-Lin Cheng, Daniel D. Mikol, Anthony J.
Windebank, Eva L. Feldman

29 Diabetes 1997 Feb;46(2):301-306
Supplemental myo-inositol prevents L-fucose-induced diabetic
neuropathy.
Sima AA, Dunlap JA, Davidson EP, Wiese TJ, Lightle RL,
Greene DA, Yorek MA
Department of Pathology, Wayne State University, Detroit,
Michigan 48236,
USA.

30 Kiuni K, Kanai S, Carrillo MC, Ivy GO. 
(-)Deprenyl increases the life span as well as activities of
superoxide dismutase and catalase but not of glutathione
peroxidase in selective brain regions in Fischer rats. 
Ann NYAcad Sci 1994;717:60-71.

31 AU: Richter C
TI: Pro-oxidants and mitochondrial Ca2+: their relationship to
apoptosis and  oncogenesis.
SO: FEBS LETTERS, 325 (1-2) 104-7  /1993 Jun 28/ 
CS: Laboratory of Biochemistry I, Swiss Federal Institute of
Technology (ETH), Zuerich.

32 AU: Knoll J
TI: Pharmacological basis of the therapeutic effect of (-)deprenyl
in  age-related neurological diseases.
SO: MEDICINAL RESEARCH REVIEWS, 12 (5) 505-24 
/1992 Sep/ 
CS: Department of Pharmacology, Semmelweis University of 
Medicine, Budapest, Hungary.

33 25.Pigeolet E, Corbisier P, Houbion A, Larnbert D, Michiels
C, Raes M, Zachary M-D, Remacle J. 
Glutathione peroxidase, superoxide dismutase,  and catalase
inactivation by  peroxides and oxygen derived free radicals. 
Mechs Ageing Devel 51:283-297, 1990.

34 AU: Hurson M; Regan MC; Kirk SJ; Wasserkrug HL; 
Barbul A
TI: Metabolic effects of arginine in a healthy elderly population.
SO: JPEN. JOURNAL OF PARENTERAL AND ENTERAL
NUTRITION, 19 (3) 227-30   /1995 May-Jun/ 

35 AU: Morales AJ; Nolan JJ; Nelson JC; Yen SS
TI: Effects of replacement dose of dehydroepiandrosterone in
men  and women of advancing age.
SO: JOURNAL OF CLINICAL ENDOCRINOLOGY AND 
METABOLISM, 78 (6) 1360-7  
CS: Department of Reproductive Medicine, University of
California School of  Medicine, La Jolla 92093-0802.

36 Klenner, Frederich R.: "Response of Peripheral and Central
Nerve  Pathology to Mega-Doses of the Vitamin B-Complex and
other Metabolites."  Journal of Applied Nutrition, Vol. 25:
Issue/34 1975.