In response to Christine Chen's question on GM1:
 
GM1 probably refers to the GM1 ganglioside, one of the
glycosphingolipids widely distributed in all tissues, but occuring in
highest concentrations in the central nervous system. It is
primarily located in the outer surface of the mammalian cell's plasma
membrane and in synaptic membranes of the CNS. GM1 ganglioside
modulates a number of cell surface and receptor activities as well as
neuronal differentiation and development, protein phosphorilation and
synaptic function.
 
The recent interest in Ganglioside GM1 in relation to PD was triggered
by an investigation by Schneider et al. (Science,Wash.DC 256:843-
846,1992) proving that the administration of Ganglioside GM1 could
induce partial recovery from experimental Parkinsonism in primates.
 
Subsequent studies discovered that:
 
1. Ganglioside GM1 does not protect against cell loss, nor the
neurochemical recovery from the striatal dopaminergic depletion
induced by MPTP in cynomolgus monkeys. However, in monkeys treated
with Ganglioside GM1 the optical density of tyrosine hydroxylase
fibers and the cellular tyrosine hydroxylase content in the remaining
cells was increased.
 
2. Motor performance of animals treated with MPTP (a dopaminergic
neurotoxin) was increased by administration of GM1 before and during
MPTP treatment. The GM1 did not prevent cell loss, but an increased
immunoreactivity of tyrosine hydroxylase in the remaining cells
suggested a possible palliative rather than curative therapy in
Parkinson's disease.
 
3. A semi synthetic sphingolipid, LIGA20, was shown to be more
effective that the parent GM1 ganglioside in exerting effects on
neurons damaged by MPTP. Striatal dopamine depletion induced by the
MPTP could be partially reversed in mice after only 4 weeks treatment
vs the 8 weeks needed for Ganglioside GM1.
 
4. Injury induced by the exitotoxic L-Dopa metabolite
2,4,5-trihydroxyphenylalanine (TOPA) to cerebellar granule cells in
vitro was limited by the simultaneous administration of LIGA20,
suggesting a therapeutic role for LIGA20 in disorders associated with
exitotoxic processes.
 
5. Motor scores in humans with chronic spinal chord injury improved
significantly after administration of Ganglioside GM1 intravenously at
a dose of 100 mg, 6 days a week for a two month period.
 
6. In Parkinson's disease the functional capacity of surviving
dopaminergic neurons of the substantia nigra is affected. The reduced
expression of tyrosine hydroxylase in these cells may be due either to
the evolving neurodegenerative process or its downregulation, possibly
secondary to chronic levidopa treatment. In MPTP treated monkeys,
neuronal survival and tyrosine hydroxylase content was not influenced
(adversely) by levidopa, but did increase with Ganglioside GM1
treatment.
 
7. Significantly more radioactive labelled Ganglioside GM1 was shown
to be present in the ventricular spaces of the brain in MPTP treated
mice vs controls 120 and 240 minutes after injection, indicating that
the administered gangliosides have the potential to reach a lesioned
CNS site.
 
8. Three to six hours after oral adminstration of LIGA20 and
Ganglioside GM1 (68 mumol/kg), the brain content of LIGA20 was shown
to be 50-fold higher than that of GM1 in rats. In contrast to GM1,
LIGA20 given orally was shown to accumulate in the brain,
resulting in pharmacological significant brain levels depending on
dose and frequency of drug administration.
 
9. Early intervention with Ganglioside GM1 was investigated in an
animal model (Weaver Mutant Mouse - cerebellar atrophy as well as
decreased numbers of substantia nigra neurons and striatal dopamine
loss), demonstrating higher striatal dopamine levels and significantly
more tyrosine hydroxylase in treated animals.
 
10. Timing of GM1 treatment seems to be important in promoting
recovery of injured neurons, depending on the degree of the initial
damage to the neurons. Timing of GM1 treatment may also be important
in brain grafting procedures and vital in the selection of the most
appropriate tissue donor age.
 
It thus appears that Ganglioside GM1, or it's analogues, may play
an important role in the treatment of Parkinsonism in future,
especially in the management and stabilization (protection?) of the
remaining dopaminergic cells.
 
Regards!
Hans
 
 
References:
 
 Schneider, J.S., Pope, A., Simpson, K., Taggart, J., Smith, M.G. and
 Distefano, L. Recovery from Experimental Parkinsonism in Primates
 with GM1 Ganglioside Treatment. Science,Wash.DC 256:843-846, 1992.
 
1.
 Herrero, M.T., Perezotano, I., Oset, C., Kastner, A., Hirsch, E.C.,
 Agid, Y., Luquin, M.R., Obeso, J.A. and Delrio, J. GM-1 Ganglioside
 Promotes the Recovery of Surviving Midbrain Dopaminergic Neurons in
 MPTP-Treated Monkeys. Neuroscience 56:965-972, 1993.
 
 
2.
 Herrero, M.T., Kastner, A., Perezotano, I., Hirsch, E.C., Luquin,
 M.R., Javoyagid, F., Delrio, J., Obeso, J.A. and Agid, Y.
 Gangliosides and Parkinsonism. Neurology 43:2132-2134, 1993.
 
3.
 Schneider, J.S. and Distefano, L. LIGA-20
 Increases Striatal Dopamine Levels in Aged MPTP- Treated Mice
 Refractory to GM1 Ganglioside Treatment. Neuroreport 5:103-104, 1993.
 
 Schneider, J.S. and Distefano, L. Oral Administration of
 Semisynthetic Sphingolipids Promotes Recovery of Striatal Dopamine
 Concentrations in a Murine Model of Parkinsonism. Neurology
 44:748-750, 1994.
 
4.
 Skaper, S.D., Fadda, E., Facci, L. and Manev, H. A Semisynthetic
 Glycosphingolipid (LIGA20) Reduces 2,4,5-trihydroxyphenylalanine
 Neurotoxicity in Primary Neuronal Cultures. Eur J Pharmacol
 243:91-93, 1993.
 
5.
 Walker, J.B. and Harris, M. GM-1 Ganglioside Administration Combined
 with Physical Therapy Restores Ambulation in Humans with Chronic
 Spinal Cord Injury. Neurosci Lett 161:174-178, 1993.
 
6.
 Kastner, A., Herrero, M.T., Hirsch, E.C., Guillen, J., Luquin, M.R.,
 Javoyagid, F., Obeso, J.A. and Agid, Y. Decreased tyrosine
 hydroxylase content in the dopaminergic neurons of MPTP-intoxicated
 monkeys: Effect of levodopa and GM1 ganglioside therapy. Ann Neurol
 36:206-214, 1994.
 
7.
 Saulino, M.F. and Schengrund, C.L. Differential
 Accumulation of Gangliosides by the Brains of MPTP-Lesioned Mice. J
 Neurosci Res 37:384-391, 1994.
 
8.
 Polo, A., Kirschner, G., Guidotti, A. and Costa, E. Brain Content of
 Glycosphingolipids After Oral Administration of Monosialogangliosides
 GM1 and LIGA20 to Rats. Mol Chem Neuropathol 21:41-53, 1994.
 
9.
 Schneider, J.S., Smith, M.G., Distefano, L. and Berrian, J. G(M1)
 Ganglioside Treatment Partially Reverses the Nigrostriatal Dopamine
 Defect in the Weaver Mutant Mouse. Brain Res 636:353-356, 1994.
 
10.
 Silani, V., Mariani, D., Donato, F.M., Ghezzi, C., Mazzucchelli, F.,
 Buscaglia, M., Pardi, G. and Scarlato, G. Development of dopaminergic
 neurons in the human mesencephalon and in vitro effects of basic
 fibroblast growth factor treatment. Exp Neurol 128:59-76, 1994.
 
 Stull, N.D., Schneider, J.S. and Iacovitti, L. GM1 Ganglioside
 Partially Rescues Cultured Dopaminergic Neurons from MPP+-Induced
 Damage - Dependence on Initial Damage and Time of Treatment. Brain
 Res 640:308-315, 1994.
 
 
 
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