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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. ===================================================================== Hans van Zyl | Cell Physiology Group | [log in to unmask] Irene Animal Production Institute | Tel: (27) 12 672 9261 Private Bag X2 | Fax: (27) 12 665 1604 IRENE 1675, South Africa | =====================================================================