IGF-I and Glycosaminoglycans Improve Peripheral Nerve Regeneration and Motor Neuron Survival in Models of Motor Neuron Disease

  • A. Gorio
  • L. Vergani
  • M. Losa
  • G. Pezzoni
  • L. Calvano
  • C. Finco
  • A. M. Di Giulio
  • A. Torsello
  • E. E. Müller


The discovery of agents capable of modulating neuronal survival and regeneration has been of interest to scientists since the early days of neuroscience. Recently, research into such agents has greatly increased due to their potential therapeutic use in neurodegenerative disorders [1]. Research related to nervous system regeneration following injury was strongly influenced by studies of Ramon Y Cajal [2] and Tello [3], and by the consolidation of the neuron theory. Tello wrote that lesioned nerves regenerate by forming sprouts which elongate, crossing the site of injury and regrowing into the distal stump up to the denervated muscle. He suggested that the processes of nerve regrowth and muscle reinnervation were promoted by some unknown substance liberated by the distal stump and/or by the denervated muscle. A tremendous advancement in this field came with the work of Levi Montalcini, Hamburgher and Cohen. Their contribution was dual: the description of neuronal death during embryonic development and the discovery of nerve growth factor [4–6]. It is now well known that at least for certain neuronal populations the process of cell death is regulated by the availability of a target-derived trophic factor. Nerve growth factor was the first of such trophic agents characterized [6]. Later it was found that the mammalian salivary gland, which corresponds to the snake venom gland, contained large amounts of nerve growth factor, and it became the most important source of the trophic factor [7]. With sufficient quantities of purified factor available, this field of research increased greatly.


Nerve Growth Factor Extensor Digitorum Longus Motor Neuron Disease Motor Neuron Survival Motoneuron Disease 


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  1. 1.
    Gorio A (1993) Neuroregeneration. Taven Press, New York.Google Scholar
  2. 2.
    Ramon y Cajal S (1928) Degeneration and regeneration of the nervous system, vol 2. Murray, LondonGoogle Scholar
  3. 3.
    Tello JF (1907) Dégéneration et regeneration des plaques motrices. Trav Lab Rech Biol Univ Madrid V: 117–149.Google Scholar
  4. 4.
    Hamburgher V (1958) Regression versus control of differentiation in motor hypoplasis. Am J Anat 102: 365–409CrossRefGoogle Scholar
  5. 5.
    Levi Montalcini R, Hamburgher V (1951) Selective growth-stimulating effects of mouse sarcoma on the sensory and sympathetic nervous system of the chick embryo. J Exp Zool 116: 321–361.CrossRefGoogle Scholar
  6. 6.
    Cohen S, Levi Montalcini R (1956) A nerve growth stimulating factor isolated from snake venom. Proc Natl Acad Sci USA 42: 571–574PubMedCrossRefGoogle Scholar
  7. 7.
    Cohen S (1960)Purification and metabolic effects of a nerve growth-promoting protein from the mouse salivary gland and its neurocytotoxic antiserum. Proc Natl Acad Sci USA 46:302–311Google Scholar
  8. 8.
    Daughaday WH, Hall K, Raben MS, Salmon JL, Van den Brand JL, Van Wyk JJ (1972) Somatomedin: a proposed designation for the “sulfation factor”. Nature 235: 107PubMedCrossRefGoogle Scholar
  9. 9.
    Lund PK, Moates-Staats BM, Hynes MA, Simmons JG, Jansen M, D’Ercole AJ, Van Wyk J J (1986) Somatomedin-C/insulin-like growth factor-II mRNAs in fetal and adult tis-sues. J Biol Chem 261: 14539–14544PubMedGoogle Scholar
  10. 10.
    Bohannon NJ, Corp ES, Wilcox BJ, Figlewicz DP, Dorsa DM, Baskin DG (1988) Localization of binding sites for insulin-like growth factor-1 (IGF-1) in the rat brain by quantitative autoradiography. Brain Res 444: 205–213PubMedCrossRefGoogle Scholar
  11. 11.
    Smith M, Clemens J, Kerchner GA, Mendelsohn LG (1988) The insulin-like growth factor-II (IGF-II) receptor of rat brain: regional distribution visualized by autoradi-ography. Brain Res 445: 241–246PubMedCrossRefGoogle Scholar
  12. 12.
    Bothwell M (1982) Insulin and somatomedin MSA promote nerve growth factor- independent neurite formation by cultured chick dorsal root ganglionic sensory neurons. J Neurosci Res 8: 225–231PubMedCrossRefGoogle Scholar
  13. 13.
    Recio-Pinto E, Rechler MM, Ishii DN (1986) Effects of insulin, insulin-like growth factor II, and nerve growth factor on neurite formation and survival in cultured sympathetic and sensory neurons. J Neurosci 6: 1211–1219PubMedGoogle Scholar
  14. 14.
    Aizenman Y, De Vellis J (1987) Brain neurons develop in a serum and glial free environment: effects of transferrin, insulin, insulin-like growth factor-I and thyroid hormone on neuronal survival, growth and differentiation. Brain Res 406: 32–42PubMedCrossRefGoogle Scholar
  15. 15.
    Caroni P, Grandes P (1990) Nerve sprouting in innervated adult skeletal muscle induced by exposure to elevated levels of insulin-like growth factors. J Cell Biol 110: 1307–1317PubMedCrossRefGoogle Scholar
  16. 16.
    Kanje M, Skottner A, Sjoberg J, Lundborg G (1989) Insulin-like growth factor-I ( IGF- I) stimulates regeneration of the rat sciatic nerve. Brain Res 486: 396–398Google Scholar
  17. 17.
    Hantai D, Akaaboune M, Lagord C, Murawsky M, Houenou LJ, Festoff BW, Vaught JL, Rieger F, Blondet B (1995) Beneficial effects of insulin-like growth factor-I on wobbler mouse motoneuron disease. J Neurol Sci 129 [Suppl]: 122–126PubMedCrossRefGoogle Scholar
  18. 18.
    Lesma E, Di Giulio AM, Ferro L, Prino G, Gorio A (1996) Glycosaminoglycans in nerve injury: I. Low doses of glycosaminoglycans promote neurite formation. J Neurosci Res 46: 565–571Google Scholar
  19. 19.
    Gorio A, Vergani L, Ferro L, Prino G, Di Giulio AM (1996) Glycosaminoglycans in nerve injury: II. Effects on transganglionic degeneration and on the expression of neurotrophic factors. J Neurosci Res 46: 572–580Google Scholar
  20. 20.
    Gorio A, Lesma E, Vergani L, Di Giulio AM (1997) Glycosaminoglycans promote nerve regeneration and muscle reinnervation. Eur J Neurosci (in press)Google Scholar
  21. 21.
    Arai T, Arai A, Busby WH Jr, Clemmons DR (1994) Glycosaminoglycans inhibit degradation of insulin-like growth factor-binding protein-5. Endocrinology 135: 2358–2363PubMedCrossRefGoogle Scholar
  22. 22.
    Arai T, Parker A, Busby WH Jr, Clemmons DR (1994) Heparin, heparan sulfate, and dermatan sulfate regulate formation of the insulin-like growth factor-I and insulinlike growth factor-binding protein complexes. J Biol Chem 269: 20388–20393PubMedGoogle Scholar
  23. 23.
    Price DL, Cleveland DW, Koliatos VE (1994) Motor neuron disease and animal models. Neurobiol Disease 1: 3–11CrossRefGoogle Scholar
  24. 24.
    Mitsumoto H, Ikeda K, Holmlund T, Greene T, Cedarbaum JM, Wong V, Lindsay RM (1994) The effects of ciliary neurotrophic factor on motor dysfunction in wobbler mouse motor neuron disease. Ann Neurol 36: 142–148PubMedCrossRefGoogle Scholar
  25. 25.
    Vergani L, Finco C, Di Giulio AM, Muller EE, Gorio A (1997) Effects of low doses of glycosaminoglycans and insulin-like growth factor-I on motor neuron disease in wobbler mouse. Neurosci Lett (in press)Google Scholar
  26. 26.
    Gorio A, Carmignoto G, Finesso M, Polato P, Nunzi MG (1983) Muscle reinnervation, II. Sprouting, synapse formation and repression. Neuroscience 8: 403–416Google Scholar
  27. 27.
    Gorio A, Marini P, Zanoni R (1983) Muscle reinnervation, III. Motoneuron sprouting capacity, enhancement by exogenous gangliosides. Neuroscience 8: 417–429Google Scholar
  28. 28.
    Messer A, Plummer J, Maskin P, Coffin JM, Frankel WN (1992) Mapping of the motor neuron degeneration Mnd gene, a mouse model of amyotrophic lateral sclerosis ( ALS ). Genomics 18: 797–802Google Scholar
  29. 29.
    Gorio A, Vergani L, De Tollis A, Di Giulio AM, Torsello A, Cattaneo L, Muller EE (1997) Muscle reinnervation following neonatal nerve crush. Interactive effects of glycosaminoglycans and insulin-like growth factor-I. Neuroscience (in press)Google Scholar
  30. 30.
    Moscatelli D (1988) Metabolism of receptor-bound and matrix-bound basic fibroblast growth factor by bovine capillary endothelial cells. J Cell Biol 107: 753–759PubMedCrossRefGoogle Scholar
  31. 31.
    Zapf J (1995) Physiological role of the insulin-like growth factor binding proteins. Eur J Endocrinol 132: 645–654PubMedCrossRefGoogle Scholar
  32. 32.
    Li Y, Milner PG, Chauhan K, Watson MA, Hoffman RM, Kodner CM, Milbrandt J, Deuel TF (1990) Cloning and expression of a developmentally regulated protein that induces mitogenic and neurite outgrowth activity. Science 250: 1690–1694PubMedCrossRefGoogle Scholar
  33. 33.
    Merenmies J, Rauvala H (1990) Molecular cloning of the 18 kDa growth-associated protein of developing brain. J Biol Chem 265: 16721–16724PubMedGoogle Scholar
  34. 34.
    Serafini T, Kennedy TE, Galko MJ, Mirzayan C, Jessel TM, Tessier-Lavigne M (1994) The netrins define a family of axon outgrowth-promoting proteins homologous to C. elegans Unc-6. Cell 78: 409–424PubMedCrossRefGoogle Scholar
  35. 35.
    Tsutsui J, Uehara K, Kadomatsu K, Matsubara S, Muramatsu T (1991) A new family of heparin-binding factors: strong conservation of midkine ( MK) sequences between the human and the mouse. Biochem Biophys Res Commun 176: 792–797Google Scholar
  36. 36.
    Yamaguchi Y (1993) Proteoglycan-growth factor interaction. Trends Glycosci Glycotechnol 5: 428–437CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Italia, Milano 1998

Authors and Affiliations

  • A. Gorio
    • 1
  • L. Vergani
    • 1
  • M. Losa
    • 1
  • G. Pezzoni
    • 1
  • L. Calvano
    • 1
  • C. Finco
    • 1
  • A. M. Di Giulio
    • 1
  • A. Torsello
    • 1
  • E. E. Müller
    • 1
  1. 1.Laboratories for Research on Pharmacology of Neurodegenerative Disorders and Neuroendocrinology, Department of Medical PharmacologyUniversity of MilanMilanItaly

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