Monosialoganglioside GM1 and Modulation of Neuronal Plasticity in CNS Repair Processes

  • Stephen D. Skaper
  • Silvio Mazzari
  • Guido Vantini
  • Laura Facci
  • Gino Toffano
  • Alberta Leon
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 296)


Today we understand the brain as a dynamic, not static, organ. Central nervous system (CNS) neurons are endowed with the capacity to react to chemical signals presented from their microenvironment with morpho-functional modifications, a process termed plasticity. This phenomenon has provided the foundation for studies directed at elucidating the pathophysiological correlates of neuronal life and death, with the ultimate objective of developing strategies to improve neurological outcome following various types of CNS insults, in particular cerebrovascular insufficiency (stroke), head and spinal trauma, and neurodegenerative diseases.


Nerve Growth Factor Middle Cerebral Artery Occlusion Excitatory Amino Acid Brain Damage Nucleus Basalis 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Agnati, L.F., Fuxe, K., Calza, K., Benfenati, F., Cavicchioli, L., Toffano, G., and Goldstein, M., 1983, Gangliosides increase the survival of lesioned nigral dopamine neurons and favour the recovery of dopaminergic synaptic function of rats by collateral sprouting, Acta Physiol, Scand., 119:347.CrossRefGoogle Scholar
  2. Argentino, C., Sacchetti, M.L., Toni, D., Savoini, G., D’Arcangelo, E., Erminio, F., Federico, F., Ferro Milone, F., Gallai, V., Gambi, D., Mamoli, A., Ottonello, G.A., Ponari, O., Rebucci, G., Senin, U., and Fieschi, C., 1989, GM1 ganglioside therapy in acute ischemic stroke, Stroke, 20:1143.PubMedCrossRefGoogle Scholar
  3. Auer, R.N., 1986, Progress review: hypoglycemic brain damage, Stroke, 17:699.PubMedCrossRefGoogle Scholar
  4. Barde, Y.A., 1989, Trophic factors and neuronal survival, Neuron, 2: 1525.PubMedCrossRefGoogle Scholar
  5. Bellato, P., Milan, F., and Toffano G., 1989, Disposition of exogenous tritium-labelled GM1 monosialoganglioside in the rat, Clin. Trials J., 26:1.Google Scholar
  6. Benveniste, H., Drejer, J., Schousboe, A., and Diemer, N.H., 1984, Elevation of the extracellular concentrations of glutamate and aspartate in rat hippocampus during transient cerebral ischemia monitored by intracerebral microdialysis, J. Neurochem., 43:1369.PubMedCrossRefGoogle Scholar
  7. Cahn, R., Borzeix, M.G., Aldinio, C., Toffano, G., and Cahn, J., 1989, Influence of monosialoganglioside inner ester on neurologic recovery after global cerebral ischemia in monkeys, Stroke, 20:652.PubMedCrossRefGoogle Scholar
  8. Casamenti, F., DiPatre, P.L., Milan, F., Petrelli, L., and Pepeu, G., 1989, Effects of nerve growth factor and GM1 ganglioside on the number and size of cholinergic neurons in rats with unilateral lesion of the nucleus basalis, Neurosci. Lett., 103:87.PubMedCrossRefGoogle Scholar
  9. Choi, D.W., 1988, Glutamate toxicity and diseases of the nervous system, Neuron, 1:623.PubMedCrossRefGoogle Scholar
  10. Collingridge, G.L., and Bliss, T.V., 1987, NMDA receptors — their role in long-term potentiation, Trends Neurosci., 10:288.CrossRefGoogle Scholar
  11. Cuello, A.C., Garofalo, L., Kenigsberg, R.L., and Maysinger, D., 1989, Gangliosides potentiate in vivo and in vitro effects of nerve growth factor on central cholinergic neurons, Proc. Natl. Acad. Sci. USA, 86:2056.PubMedCrossRefGoogle Scholar
  12. Cuello, A.C., Stephens, P.H., Tagari, P.C., Sofroniew, M.V., and Pearson, R.C.A., 1986, Retrograde changes in the nucleus basalis of the rat, caused by cortical damage, are prevented by exogenous ganglioside GM1, Brain Res., 376:373.PubMedCrossRefGoogle Scholar
  13. Dal Toso, R., Skaper S.D., Ferrari, G., Vantini G., Toffano, G., and Leon, A., 1988, Ganglioside involvement in membrane-mediated transfer of trophic information. Relationship to GM1 effects following CNS injury, in: “Pharmacological Approaches to the Treatment of Spinal Cord Injury,” D.G. Stein and B.A. Sabel, eds., Plenum Press, New York.Google Scholar
  14. DiPatre, P.L., Casamenti, F., Cenni, A., and Pepeu, G., 1989, Interaction between nerve growth factor and GM1 monosialoganglioside in preventing cortical choline acetyltransferase and high affinity choline uptake decrease after lesion of the nucleus basalis, Brain Res., 480:219.PubMedCrossRefGoogle Scholar
  15. Doherty, P., Dickson, J.G., Flanigan, T.P., and Walsh, F.S., 1985, Ganglioside GM1 does not initiate, but enhances neurite regeneration of nerve growth factor-dependent sensory neurons, J. Neurochem., 44:1259.PubMedCrossRefGoogle Scholar
  16. Facci, L., Leon, A., Toffano, G., Sonnino, S., Ghidoni, R., and Tettamanti, G., 1984, Promotion of neuritogenesis in mouse neuroblastoma cells by exogenous gangliosides. Relationship between the effect and the cell association of ganglioside GM1, J. Neurochem., 42:299.PubMedCrossRefGoogle Scholar
  17. Facci, L., Leon, A., and Skaper, S.D., 1990a, Excitatory amino acid neurotoxicity in cultured retinal neurons: involvement of N-methyl-D-aspartate (NMDA) and non-NMDA receptors and effect of ganglioside GM1, J. Neurosci. Res., in press.Google Scholar
  18. Facci, L., Leon, A., and Skaper, S.D., 1990b, Hypoglycemic neurotoxicity in vitro: involvement of excitatory amino acid receptors and attenuation by monosialoganglioside GM1, Neuroscience, in press.Google Scholar
  19. Favaron, M., Manev, H., Alho, H., Bertolino, M., Ferret, B., Guidotti, A., and Costa, E., 1988, Gangliosides prevent glutamate and kainate neurotoxicity in primary neuronal cultures of neonatal rat cerebellum and cortex, Proc. Natl. Acad. Sci. USA, 85:7351.PubMedCrossRefGoogle Scholar
  20. Ferrari, G., Fabris, M., and Gorio, A., 1983, Gangliosides enhance neurite outgrowth in PC12 cells, Dev. Brain Res., 8:215.CrossRefGoogle Scholar
  21. Ghidoni, R., Fiorilli, A., Trinchera, M., Venerando, B., Chigorno, V., and Tettamanti, G., 1989, Uptake, cell penetration and metabolic processing of exogenously administered GM1 ganglioside in rat brain, Neurochem. Internatl., 15:455.CrossRefGoogle Scholar
  22. Hadjiconstantinou, M., Rosetti, Z.L., Paxton, R.C., and Neff, N.H., 1986, Administration of GM1 ganglioside restores the dopamine content in striatum after chronic treatment with MPTP, Neuropharmacology, 25:1075.PubMedCrossRefGoogle Scholar
  23. Hadjiconstantinou, M., Yates, A.J., and Neff, N.H., 1990, Hypoxia-induced neurotransmitter deficits in neonatal rats are partially corrected by exogenous GM1 ganglioside, J. Neurochem., 55:864.PubMedCrossRefGoogle Scholar
  24. Karpiak, S.E., Li, Y.S., and Mahadik, S.P., 1987, Gangliosides (GM1 and AGF2) reduce mortality due to ischemia: protection of membrane function, Stroke, 18:184.PubMedCrossRefGoogle Scholar
  25. Karpiak, S.E., Vilim, F., and Mahadik, S.P., 1984, Gangliosides accelerate rat neonatal learning and levels of cortical acetylcholinesterases, Dev. Neurosci., 6:127.CrossRefGoogle Scholar
  26. Karpiak, S.E., Mahadik, S.P., and Wakade, C.G., 1990, Ganglioside reduction of ischemic injury, CRC Crit. Rev. Neurobiol., 5:221.Google Scholar
  27. Komatsumoto, S., Greenberg, J.H., Hickey, W.F., and Reivich, M., 1988, Effect of the ganglioside GM1 on neurologic function, electroencephalogram amplitude, and histology in chronic middle cerebral artery occlusion in cats. Stroke, 19:1027.PubMedCrossRefGoogle Scholar
  28. Katoh-Semba, R., Skaper, S.D., and Varon, S., 1984, Interaction of GM1 ganglioside with PC12 pheochromocytoma cells: serum-and NGF-dependent effects on neuritic growth (and proliferation), J. Neurosci. Res., 12:299.PubMedCrossRefGoogle Scholar
  29. Krakun, I., Rösner, H., and Cosovic, C., 1986, Topographical distribution of the gangliosides in the developing and adult human brain, in: “Gangliosides and Neuronal Plasticity,” G. Tettamanti, R.W. Ledeen, K. Sandhoff, Y. Nagai, and G. Toffano, eds., Fidia Research Sereies, Vol. 6, Liviana Press, Padova.Google Scholar
  30. Ledeen, R.W., 1983, Gangliosides, in: “Handbook of Neurochemistry,” A. Lajtha, ed., Plenum Press, New York.Google Scholar
  31. Leon, A., Facci, L., Toffano, G., Sonnino, S., and Tettamanti, G., 1981, Activation of (Na+, K+) ATPase by nanomolar concentrations of GM1, J. Neurochem., 37:350.PubMedCrossRefGoogle Scholar
  32. Leon, A., Facci, L., Benvegnù, D., and Toffano, G., 1982, Morphological and biochemical effects of gangliosides in neuroblastoma cells, Dev. Neurosci., 5:108.PubMedCrossRefGoogle Scholar
  33. Leon, A., Benvegnù, D., Dal Toso, R., Presti, D., Facci, L., Giori, O., and Toffano, G., 1984, Dorsal root ganglia and nerve growth factor: a model for understanding the mechanism of GM1 effects on neuronal repair, J. Neurosci. Res., 12:277.PubMedCrossRefGoogle Scholar
  34. Leon, A., Dal Toso, R., Presti, D., Benvegnù, D., Facci, L., Kirschner, G., Tettamanti, G., and Toffano, G., 1988, Development and survival of neurons in dissociated fetal mesencephalic serum-free cell cultures: II. Modulatory effects of gangliosides, J. Neurosci., 8:746.PubMedGoogle Scholar
  35. Levi-Montalcini, R., 1987, The nerve growth factor thirty five years later, Science, 237:1154.PubMedCrossRefGoogle Scholar
  36. Lipartiti, M., Mazzari, S., Lazzaro, A., Zanoni, R., Seren, M.S., and Leon, A., 1989, Monosialogangliosides reduce NMDA neurotoxicity in neonatal rats, Soc. Neurosci. Abstr., 15:764.Google Scholar
  37. Lombardi, G., Zanoni, R., and Moroni, F., 1989, Systemic treatments with GM1 ganglioside reduce quinolinic acid-induced striatal lesions in the rat, Eur. J. Pharmacol., 174:123.PubMedCrossRefGoogle Scholar
  38. Mahadik, S.P., and Karpiak, S.E., 1986, GM1 ganglioside enhances neonatal cortical development, Neurotoxicology, 7:161.PubMedGoogle Scholar
  39. Mahadik, S.P., Vilim, F., Korenvosky, A., and Karpiak, S.E., 1988, GM1 ganglioside protects nucleus basalis from excitotoxin damage: reduced cortical cholinergic losses and animal mortality, J. Neurosci. Res., 20:479.PubMedCrossRefGoogle Scholar
  40. Manev, H., Favaron, M., Guidotti, A., and Costa, E., 1989, Delayed increase of Ca2+ influx elicited by glutamate: role in neuronal death, Mol. Pharmacol., 36:106.PubMedGoogle Scholar
  41. Milani, D., Guidolin, D., Facci, L., Pozzan, T., Buso, M., Leon, A., and Skaper, S.D., 1990, Excitatory amino acid-induced alterations of cytoplasmic free Ca2+ in individual cerebellar granule neurons: role in neurotoxicity, J. Neurosci. Res., in press.Google Scholar
  42. Morris, R.G.M., 1989, Synaptic plasticity and learning: selective impairment of learning in rats and blockage of long-term potentiation in vivo by the N-methyl-D-aspartate receptor antagonist AP5, J. Neurosci., 9:3040.PubMedGoogle Scholar
  43. Olney, J.W., Labruyere, J., and Price, M.T., 1989, Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs, Science, 244:1360.PubMedCrossRefGoogle Scholar
  44. Petroni, A., Bertazzo, A., Sarti, S., and Galli, C., 1989, Accumulation of arachidonic acid cyclo- and lipoxygenase products in rat brain during ischemia and reperfusion: effects of treatment with GM1-lactone, J. Neurochem., 53:747.PubMedCrossRefGoogle Scholar
  45. Purpura, D.P., and Baker, H.J., 1977, Neurite induction in mature cortical neurones in feline GM1 ganglioside storage disease. Nature, 266:553.PubMedCrossRefGoogle Scholar
  46. Rothman, S.M., and Olney, J.W., 1986, Glutamate and the pathophysiology of hypoxic/ischemic brain damage, Ann. Neurol., 19:105.PubMedCrossRefGoogle Scholar
  47. Sabel, B.A., Slavin, M.D., and Stein, D.G., 1984, GM1 ganglioside treatment facilitates behavioral recovery from bilateral brain damage, Science, 225:340.PubMedCrossRefGoogle Scholar
  48. Seren, M.S., Rubini, R., Lazzaro, A., Zanoni, R., Fiori, M.G., and Leon, A., 1990, Protective effects of the inner ester derivative of monosialoganglioside following transitory forebrain ischemia in rats, Stroke, in press.Google Scholar
  49. Shigeno, T., and Mima, T., 1988, Prevention of hippocampal cell death after cerebral ischemia by intraventricular administration of nerve growth factor, in: “Proceedings of the International Symposium on Alzheimer’s Disease”, H. Saininen, ed., University of Kuopio Press, Kuopio (abstract).Google Scholar
  50. Skaper, S.D., and Varon, S., 1985, Ganglioside GM1 overcomes serum inhibition of neuritic outgrowth, Internatl. J. Dev. Neurosci., 3:187.CrossRefGoogle Scholar
  51. Skaper, S.D., Katoh-Semba, R., and Varon, S., 1985, GM1 ganglioside accelerates neurite outgrowth from primary peripheral and central neurons under selected culture conditions, Dev. Brain Res., 23:19.CrossRefGoogle Scholar
  52. Skaper, S.D., Leon, A., and Toffano, G., 1989a, Ganglioside function in the development and repair of the nervous system: from basic science to clinical application, Mol. Neurobiol., 3:173.PubMedCrossRefGoogle Scholar
  53. Skaper, S.D., Facci, L., Milani, D., and Leon, A., 1989b, Monosialoganglioside GM1 protects against anoxia-induced neuronal death in vitro, Exp. Neurol., 106:297.PubMedCrossRefGoogle Scholar
  54. Skaper, S.D., Facci, L., and Leon, A., 1990, Gangliosides attenuate the delayed neurotoxicity of aspartic acid in vitro, Neurosci. Lett., in press.Google Scholar
  55. Spoerri, P.E., 1986, Facilitated establishment of contacts and synapses in neuronal cultures: ganglioside-mediated neurite sprouting and outgrowth, in: “Gangliosides and Neuronal Plasticity,” G. Tettamanti, R.W. Ledeen, K. Sandhoff, Y. Nagai, and G. Toffano, eds., Fidia Research Series, Vol. 6, Liviana Press, Padova.Google Scholar
  56. Svennerholm, L., 1963, Chromatographic separation of human brain gangliosides, J. Neurochem., 10:613.PubMedCrossRefGoogle Scholar
  57. Toffano, G., Savoini, G., Moroni, F., Lombardi, G., Calzà, L., and Agnati, L.F., 1983, GM1 ganglioside stimulates regeneration of dopaminergic neurons in the central nervous system, Brain Res., 261:163.PubMedCrossRefGoogle Scholar
  58. Vaccarino, F., Guidotti, A., and Costa, E., 1987, Ganglioside inhibition of glutamate-mediated protein kinase C translocation in primary cultures of cerebellar neurons, Proc. Natl. Acad. Sci. USA, 84:8707.PubMedCrossRefGoogle Scholar
  59. Vantini, G., Fusco, M., Bigon, E., and Leon, A., 1988, GM1 ganglioside potentiates the effect of nerve growth factor in preventing vinblastine-induced sympathectomy in newborn rats, Brain Res., 488:252.CrossRefGoogle Scholar
  60. Weihmuller, F.B., Hadjicontantinou, M., Bruno, J.P., and Neff, N.H., 1988, Administration of GM1 ganglioside eliminates neuroleptic-induced sensorimotor deficits in MPTP-treated mice, Neurosci. Lett., 92:207.PubMedCrossRefGoogle Scholar
  61. Willinger, M., and Schachner, M., 1980, GM1 ganglioside as a marker for neuronal differentiation in mouse cerebellum, Dev. Biol., 74:101.PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1991

Authors and Affiliations

  • Stephen D. Skaper
    • 1
  • Silvio Mazzari
    • 1
  • Guido Vantini
    • 1
  • Laura Facci
    • 1
  • Gino Toffano
    • 1
  • Alberta Leon
    • 1
  1. 1.Fidia Research LaboratoriesAbano TermeItaly

Personalised recommendations