Regeneration in the Central Nervous System: Concepts and Facts

  • L. F. Agnati
  • I. Zini
  • M. Zoli
  • K. Fuxe
  • E. Merlo Pich
  • R. Grimaldi
  • G. Toffano
  • M. Goldstein
Part of the Advances and Technical Standards in Neurosurgery book series (NEUROSURGERY, volume 16)


In many years, based on Cajal’s statement “… nerve paths are fixed, ended, immutable. Everything may die, nothing may be regenerated…” (Ramon y Cajal 1928) it has been assumed that the central nervous system (CNS) is unable to regenerate a lesioned pathway. Current opinion is in many instances the opposite (Liu and Chambers 1958; Fuxe et al. 1974; Cotman 1978; Björklund and Stenevi 1979). There is now a general belief in possible regeneration in the CNS, even if clearcut results remain scarce (Finger and Almli 1985; Berry 1985). In fact, in some cases, functional recovery after a CNS lesion has been observed and correlated with a morphological readjustment of the neural circuitry. However, a cause-effect link between morphological and functional recovery has not yet been provided, at least not beyond any doubt (Finger and Almli 1985). Since, as a general rule, for both invertebrates and vertebrates, there is little or no further generation of nerve cells in the mature brain, the morphological recovery observed after a lesion must rely on the ability of neurons to form new processes and new contacts (Raisman and Field 1973; Goldberg 1980; Veraa and Grafstein 1981). In fact, neuronal connections are in a dynamic state (morphological plasticity), since also in physiological conditions in the mature brain they are subjected to continuous remodelling (Björklund and Stenevi 1979; Cotman et al. 1981; Cotman and Nieto-Sampedro 1984).


Nerve Growth Factor Functional Recovery Nigrostriatal Pathway Nerve Growth Factor mRNA Striatal Level 
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  1. 1.
    Agnati LF, Fuxe K, Calza L, Benfenati F, Cavicchioli L, Toffano G, 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: 347–363PubMedGoogle Scholar
  2. 2.
    Agnati LF, Fuxe K, Benfenati F, Zini L, Zoli M, Fabbri L, Härfstrand A (1984a) Computer assisted morphometry and microdensitometry of transmitter identified neurons with special reference to the mesostriatal dopamine pathway. I. Methodological aspects. Acta Physiol Scand [Suppl] 532: 5–36Google Scholar
  3. 3.
    Agnati LF, Fuxe K, Calza L, Goldstein M, Toffano G, Giardino L, Zoli M (1984b) Computer assisted morphometry and microdensitometry of transmitter identified neurons with special reference to the mesostriatal dopamine pathway. II. Further studies on the effects of the GM 1 ganglioside on the degenerative and regenerative features of mesostriatal dopamine neurons. Acta Physiol Scand [Suppl] 532: 37–42Google Scholar
  4. 4.
    Agnati LF, Fuxe K, Benfenati F, Zoli M, Owman C, Diemer NH, Kâhrström JK, Toffano G, Cimino M (1985a) Effects of ganglioside GM 1 treatment on striatal glucose metabolism, blood flow, and protein phosphorylation of the rat. Acta Physiol Scand 125: 43–53Google Scholar
  5. 5.
    Agnati LF, Fuxe K, Davalli P, Zini I, Corti A, Zoli M (1985b) Striatal ornithine decarboxylase activity following neurotoxic and mechanical lesions of the mesostriatal dopamine system of the male rat. Acta Physiol Scand 125: 173–175Google Scholar
  6. 6.
    Agnati LF, Fuxe K, Toffano G, Calza L, Zini I, Giardino L, Mascagni F, Goldstein M (1985c) Effects of chronic GM 1 ganglioside treatment on nigral dopamine cell bodies and dendrites in experimental rats using image analysis. Relationship to the pharmacological properties. In: Agnati LF, Fuxe K (eds) Quantitative neuroanatomy in transmitter research. Macmillan Press, London, pp 145–156Google Scholar
  7. 7.
    Agnati LF, Fuxe K, Zini I, Davalli P, Corti A, Calza L, Toffano G, Zoli M, Piccinini G, Goldstein M (1985d) Effects of lesions and ganglioside GM 1 treatment on striatal polyamine levels and nigral DA neurons. A role of putrescine in the neurotropic activity of gangliosides. Acta Physiol Scand 124: 499–506Google Scholar
  8. 8.
    Agnati LF, Fuxe K, Zoli M, Davalli P, Corti A, Zini I, Toffano G (1985e) Effects of neurotoxic and mechanical lesions of the mesostriatal dopamine pathway on striatal polyamine levels in the rat: modulation by chronic ganglioside GM 1 treatment. Neurosci Lett 61: 339–344Google Scholar
  9. 9.
    Agnati LF, Fuxe K, Zoli M, Merlo Pich E, Benfenati F, Zini I, Goldstein M (1986a) Aspects on the information handling by the central nervous system: focus on cotransmission in the aged rat brain. In: Hökfelt T, Fuxe K, Pernow B (eds) Coexistence of neuronal messengers: a new principle in chemical transmission. Prog Brain Res, vol 68. Elsevier, Amsterdam, pp 291–301Google Scholar
  10. 10.
    Agnati LF, Fuxe K, Zoli M, Zini I, Toffano G, Ferraguti F (1986b) A correlation analysis of the regional distribution of central enkepahlin and 13- endorphin immunoreactive terminals and of opiate receptors in adult and old male rats. Evidence for the existence of two main types of communication in the central nervous system: the volume transmission and the wiring transmission. Acta Physiol Scand 128: 201–207Google Scholar
  11. 11.
    Aguayo AJ (1985) Capacity for renewed axonal growth in the mammalian central nervous system. In: Bignami A, Bloom FE, Bolis CL, Adeloye A (eds) Central nervous system plasticity and repair. Raven Press, New York, pp 31–40Google Scholar
  12. 12.
    Aguayo AJ, Dikson R, Trecarten J, Attwell M, Bray GM, Richardson P (1978) Ensheathment and myelination of regenerating PNS fibers by transplanted optic nerve glia. Neurosci Lett 9: 97–104PubMedGoogle Scholar
  13. 13.
    Aguayo AJ, Bray GM, Perkins CS, Duncan ID (1979) Axon-sheath cell interactions in peripheral and central nervous system transplant. Soc Neurosci Symp 4: 361–383Google Scholar
  14. 14.
    Alberts B, Bray D, Lewis J, Raff M, Roberts K, Watson JD (1983) Molecular biology of the cell. Garland Publishing Inc, New YorkGoogle Scholar
  15. 15.
    Austin L (1985) Molecular aspect of nerve regeneration. In: Lajtha A (ed) Handbook of neurochemistry. Plenum Press, New York, pp 1–29Google Scholar
  16. 16.
    Barbin G, Manthorpe M, Varon S (1984) Purification of the chick eye Ciliary Neuronotrophic Factor (CNTF). J Neurochem 43: 1468–1478PubMedGoogle Scholar
  17. 17.
    Bachrach U (1973) Function of naturally occurring polyamines. Academic Press, New YorkGoogle Scholar
  18. 18.
    Barde YA, Edgar D, Thoenen H (1982) Purification of a new neuronotrophic factor from mammalian brain. EMBO J 1: 549–553PubMedGoogle Scholar
  19. 19.
    Benoit P, Changeux JP (1978) Consequences of blocking the nerve with a local anaesthetic on the evolution of multi-innervation in developing rat soleus muscle. Brain Res 149: 89–96PubMedGoogle Scholar
  20. 20.
    Berg KD (1984) New neuronal growth factors. Ann Rev Neurosci 7: 149–170PubMedGoogle Scholar
  21. 21.
    Berry M (1982) Post-injury myelin-breakdown products inhibit axonal growth: an hypothesis to explain the failure of axonal regeneration in the mammalian central nervous system. In: Berry N (ed) Growth and regeneration of axon in the nervous system. Bibliotheca Anatomica, vol 23. Karger, Basel, pp 1–11Google Scholar
  22. 22.
    Berry M (1985) Regeneration and plasticity in the CNS. In: Swash M, Kennard C (eds) Scientific basis of clinical neurology. Churchill Livingstone, London, pp 658–679Google Scholar
  23. 23.
    Bernstein JJ, Bernstein ME (1967) Effect of glia-ependymal scar and teflon arrest on the regeneration capacity of goldfish spinal cord. Exp Neurol 19: 25–32PubMedGoogle Scholar
  24. 24.
    Bernstein JJ, Bernstein ME (1973) Neuronal alteration and reinnervation following axonal regeneration and sprouting in mammalian cord. Brain Behav Evol 8: 135–161PubMedGoogle Scholar
  25. 25.
    Bessou P, Laporte Y, Pages B (1966) Observation sur la re-innervation de fuseaux neuro-musculaires de chat. CR Soc Biol, Paris 160: 408–411Google Scholar
  26. 26.
    Björklund A, Stenevi U (1979) Regeneration of monoaminergic and cholinergic neurons in the mammalian central nervous system. Physiol Rev 59: 62–100PubMedGoogle Scholar
  27. 27.
    Björklund A, Dunnett SB, Stenevi U, Lewis ME, Iversen SD (1980) Rein-nervation of the denervated striatum by substantia nigra transplants: functional consequences as revealed by pharmacological sensorimotor testing. Brain Rés 199: 307–333PubMedGoogle Scholar
  28. 28.
    Björklund A, Stenevi U (1984) Intracerebral neural implant: neuronal replacement and reconstruction of damaged circuitries. Ann Rev Neurosci 7: 279–308PubMedGoogle Scholar
  29. 29.
    Bijlsma WA, Jennekens FGI, Schotman P, Gispen WH (1982) Stimulation by ACTH(4–10) of nerve fibre regeneration following sciatic nerve crush. Muscle and Nerve 6: 102–110Google Scholar
  30. 30.
    Carpenter G, Cohen S (1978) Epidermal growth factor. In: Litwak G (ed) Biochemical actions of hormones. Academic Press Inc, New York, pp 203–247Google Scholar
  31. 31.
    Cintra A, Fuxe K, Agnati LF, Persson L, Härfstrand A, Zoli M, Eneroth P, Zini I (1987) Evidence for the existence of ornithine decarboxylase-immunoreactive neurons in the rat brain. Neurosci Lett 76: 269–274PubMedGoogle Scholar
  32. 32.
    Clark WE LeGros (1943) The problem of neuronal regeneration in the central nervous system. II. The insertion of peripheral stumps into the brain. J Anat 73: 251–259Google Scholar
  33. 33.
    Clemente CD (1964) Regeneration in the vertebrate central nervous system. Int Rev Biol 6: 257–301Google Scholar
  34. 34.
    Cohen SS (1971) Introduction to the polyamines. Prentice Hall, Englewood Cliffs, New JerseyGoogle Scholar
  35. 35.
    Cotman CW (1978) Neuronal plasticity. Raven Press, New YorkGoogle Scholar
  36. 36.
    Cotman CW, Nieto-Sampedro M, Harris EW (1981) Synapse replacement in the nervous system of adult vertebrates. Physiol Rev 61: 684–784PubMedGoogle Scholar
  37. 37.
    Cotman CW, Nieto-Sampedro M (1984) Cell biology of synaptic plasticity. Science 225: 1287–1294PubMedGoogle Scholar
  38. 38.
    Cowan WM, Fawcett JW, O’Leary DM, Stanfield BB (1984) Regressive events in neurogenesis. Science 225: 1258–1265PubMedGoogle Scholar
  39. 39.
    Crutcher KA, Collins F (1982) In vitro evidence for two distinct hippocampal growth factors: basis of neuronal plasticity? Science 217: 67–70PubMedGoogle Scholar
  40. 40.
    Cuello AC, Stephens PH, Sofroniew MV, Pearson RCA, Tagari P, Powell TP (1985) Effects of gangliosides on cholinergic neurones of the nucleus basalis following unilateral cortical lesion. In: Neuronal plasticity and gangliosides. International Society for Neurochemistry, Mantova, Italy, May 29–31, pp 49Google Scholar
  41. 41.
    Dahlström A, Fuxe K (1964) Evidence for the existence of monoamine-containing neurons in the central nervous system. I. Demonstration of monoamines in the cell bodies of brain stem neurons. Acta Physiol Scand 62 [Suppl] 232: 1–55Google Scholar
  42. 42.
    Dahlström A, Fuxe K (1965) Evidence for the existence of monoamine-containing neurons in the central nervous system. II. Experimentally induced changes in the intraneuronal amine levels of bulbospinal neuron systems. Acta Physiol Scand 64 [Suppl] 247: 1–36Google Scholar
  43. 43.
    David S, Aguayo AJ (1981) Axonal elongation into peripheral neurons system “bridges” after central nervous system injury in adult rats. Science 214: 931–933PubMedGoogle Scholar
  44. 44.
    Davis GE, Skaper SD, Manthorpe M, Moonen G, Varon S (1984) Serum-mediated inhibition of neurite growth from ciliary ganglion neurons in vitro. J Neurosci Res 12: 29–40PubMedGoogle Scholar
  45. 45.
    Doolittle RF, Hunkapiller MW, Hood LE, Davare SG, Robbins KC, Aaronson SA, Hantoniades HN (1983) Simian sarcoma virus ONC gene vsis is derived from the gene (or genes) encoding a platelet-derived growth factor. Science 221: 275–277PubMedGoogle Scholar
  46. 46.
    Dunnett SB, Björklund A, Stenevi U, Iversen SD (1981) Behavioural recovery following transplantation of substantia nigra in rats subjected to 6OHDA lesions of the nigrostriatal pathway. I. Unilateral lesions. Brain Res 215: 147–161PubMedGoogle Scholar
  47. 47.
    Edwards PM, Van der Zee CEEM, Verhaagen J, Schotman FGI, Jennekens FGI, Gispen WH (1984) Evidence that the neurotrophic actions of a-MSH may derive from its hability to mimic the actions of a polypeptide formed in degeneration nerve stumps. J Neurol Sci 64: 333–340PubMedGoogle Scholar
  48. 48.
    Edwards PM, Verhaagen J, Spierings T, Schotman P, Jennekens FGI, Gispen WH (1985) The effect of ACTH4–10 on protein synthesis, actin and tubulin during regeneration. Brain Res Bull 15: 267–272PubMedGoogle Scholar
  49. 49.
    Ek B, Wastermark B, Wateson A, Heldin CH (1982) Stimulation of tyrosine-specific phosphorylation by platelet-derived growth factor. Nature (London) 295: 419–420Google Scholar
  50. 50.
    Fallon JH, Seroogy KB, Loughlin SE, Morrison RS, Bradshaw RA, Knauer DJ, Cunningham DD (1984) Epidermal Growth Factor immunoreactive material in the central nervous system: location and development. Science 224: 1107–1109PubMedGoogle Scholar
  51. 51.
    Finger S, Almli CR (1985) Brain damage and neuroplasticity: mechanism of recovery or development? Brain Res Rev 10: 177–186Google Scholar
  52. 52.
    Fuxe K, Jonsson G, Nygren LG, Olson L (1974) Studies on central 5hydroxytriptamine neurons using dihydroxytriptamines: evidence for regeneration of bulbospinal 5-hydroxytriptamine axons and terminals. In: Fuxe K, Olson L, Zotterman Y (eds) Dynamics of degeneration and growth of neurons. Pergamon Press, London, pp 169–179Google Scholar
  53. 53.
    Gash D, Sladek J (1980) Functional development of grafted vasopressin neurons. Science 210: 1367–1369PubMedGoogle Scholar
  54. 54.
    Gearhart J, Oster-Granite ML, Guth L (1979) Histological and functional changes after transection of the spinal cord of fetal and neonatal mice. Exp Neurol 66: 1–15PubMedGoogle Scholar
  55. 55.
    Gilad GM, Gilad VH (1983) Polyamine biosynthesis is required for survival of sympathetic neurons after axonal injury. Brain Res 273: 191–194PubMedGoogle Scholar
  56. 56.
    Gnahn H, Hefti F, Heumann R, Schwab ME, Thoenen H (1983) NGF mediated increase of choline acetyltransferase (ChAT) in the neonatal rat forebrain: evidence for a physiological role for NGF in the brain? Dev Brain Res 9: 45–52Google Scholar
  57. 57.
    Goedert M, Fine A, Hunt SP, Ullrich A (1986) Nerve Growth Factor mRNA in peripheral and central rat tissues and in the human central nervous system: lesion effects in the rat brain and levels in Alzheimer disease. Mol Brain Res 1: 85–92Google Scholar
  58. 58.
    Goldberg ME (1980) Motor recovery after lesion. Trends Neurosci 29: 288–291Google Scholar
  59. 59.
    Gospodarowicz D, Cheng J, Lui GM, Baird A, Bohlent P (1984) Isolation of brain fibroblast growth factor by heparin-Sephadex affinity chromatography: identity with pituitary fibroblast growth factor. Proc Natl Acad Sci USA 81: 6963–6967PubMedGoogle Scholar
  60. 60.
    Gutmann E, Young JZ (1944) Reinnervation of muscle after various periods of atrophy. J Anat 78: 1543–1544Google Scholar
  61. 61.
    Hansson HA, Dahlin LB, Danielsen N, Fryklund L, Nachemson AK, Polleryd P, Rozell B, Skottner A, Stemme S, Lundborg GL (1986) Evidence indicating trophic importance of IGF-I in regenerating peripheral nerves. Acta Physiol Scand 126: 609–614PubMedGoogle Scholar
  62. 62.
    Hefti F (1986) Nerve Growth Factor promotes survival of septal cholinergic neurons after fimbrial transections. J Neurosci 6: 2155–2162PubMedGoogle Scholar
  63. 63.
    Herrera-Marschitz M, Stromberg I, Olsson D, Ungerstedt U, Olson L (1984) Adrenal medullary implants in the dopamine-denervated rat striatum. II. Acute behavior as a function of graft amount of location and its modulation by neuroleptics. Brain Res 297: 53–61PubMedGoogle Scholar
  64. 64.
    Herschman HR (1986) Polypeptide growth factors and the CNS. Trends Neurosci 91: 53–57Google Scholar
  65. 65.
    Hess A (1956) Reactions of mammalian fetal spinal cord, spinal ganglia and brain to injury. J Exp Zool 132: 349–374Google Scholar
  66. 66.
    Hilbig R, Lauke G, Rahmann H (1983/84) Brain gangliosides during the life span (embryogenesis to senescence) of the rat. Dev Neurosci 6: 260–270PubMedGoogle Scholar
  67. 67.
    Hosobuchi Y, Baskin DS, Woo SK (1982) Reversal of induced ischemic neurologic deficit in gerbils by the opiate antagonist naloxone. Science 215: 69–71PubMedGoogle Scholar
  68. 68.
    Huff KR, Schreier W (1985) Modulation of astrocyte responses by Epidermal Growth Factor, Fibroblast Growth Factor and Platelet-Derived Growth Factor. In: Society for Neuroscience, 15th annual meeting. Dallas, Texas, pp 291(6)Google Scholar
  69. 69.
    Jackson PC (1983) Reduced activity during development delays the normal rearrangement of synapses in the rabbit ciliary ganglion. J Physiol (London) 345: 319–327Google Scholar
  70. 70.
    Jacob H (1963) CNS tissue and cellular pathology. In: Schade P, McMenemy B (eds) Selective vulnerability of the brain in hypoxemia. Davis Co, Philadelphia, pp 153–174Google Scholar
  71. 71.
    Jacobson M (1978) Developmental neurobiology. Plenum Press, New YorkGoogle Scholar
  72. 72.
    Janson AM, Agnati LF, Kitayama I, Härfstrand A, Andersson K, Goldstein M, Fuxe K (1988) Chronic nicotine treatment counteracts the disappearance of tyrosine-hydroxylase immunoreactive nerve cell bodies, dendrites and terminals in the mesostriatal DA system of the male rat after partial hemitransection. Brain Res, in press.Google Scholar
  73. 73.
    Jonsson G, Sachs C, (1972) Neurochemical properties of adrenergic nerves regenerated after 6-hydroxy-dopamine. J Neurochem 19: 2577–2585PubMedGoogle Scholar
  74. 74.
    Jonsson G, Pycock C, Sachs C (1973) Plastic changes of central noradrenergic neurons after 6-hydroxydopamine. In: Usdin E, Snyder S (eds) Frontiers in catecholamine research. Pergamon Press, New York, pp 459–461Google Scholar
  75. 75.
    Jonsson G, Pycock C, Fuxe K, Sachs C (1974) Changes in the development of central noradrenaline neurons following neonatal administration of 6hydroxydopamine. J Neurochem 22: 621–626Google Scholar
  76. 76.
    Jonsson G, Gorio A, Hallman D, Janigro H, Kojima H, Luthman J, Zanoni R (1984) Effects of GM 1 Ganglioside on developing and mature serotonin and noradrenaline neurons lesioned by selective neurotoxins. J Neurosci Res 12: 459–475PubMedGoogle Scholar
  77. 77.
    Kalil K, Reh T (1979) Regrowth of severed axons in the neonatal central nervous system: establishment of normal connections. Science 205: 1158–1161PubMedGoogle Scholar
  78. 78.
    Kandel ER (1985) Synapse formation, trophic interactions between neurons and the development of behavior. In: Kandel ER, Schwartz JH (eds) Principles of neural science, 2nd edition. Elsevier, New YorkGoogle Scholar
  79. 79.
    Karpiak SE (1983) Accelerated functional development in the rat neonate following ganglioside administration. In: The cell biology of neuronal plasticity, Fidia Research Series/Frontiers in Neuroscience, n. 1, pp 91–92Google Scholar
  80. 80.
    Karsarskis J, Karpiak SE, Rapport MM, Yu RK, Bass NH (1981) Abnormal maturation of cerebral cortex and behavioral deficit in adult rats after neonatal administration of antibodies to gangliosides. Dev Brain Res 1: 25–35Google Scholar
  81. 81.
    Kiernan JA (1979) Hypotheses concerned with axonal regeneration in the mammalian nervous system. Biol Rev 54: 155–197PubMedGoogle Scholar
  82. 82.
    Kligman D (1982) Isolation of a protein from bovine brain which promotes neurite extension from chick embryo cerebral cortex neurons in definite medium. Brain Res 250: 93–100PubMedGoogle Scholar
  83. 83.
    Kogure K, Siesjö BK, Welsh FA (1985) Molecular mechanism of ischemic brain damage. Prog Brain Res, vol 63. Elsevier Press, New YorkGoogle Scholar
  84. 84.
    Kojima H, Gorio A, Janigro D, Jonsson G (1984) GM 1 ganglioside enhances regrowth of noradrenaline nerve terminals in rat cerebral cortex lesioned by the neurotoxin 6-hydroxydopamine. Neuroscience 13: 1011–1022PubMedGoogle Scholar
  85. 85.
    König JFR, Klippel RE (1963) The rat brain. A stereotaxic atlas of the forebrain and lower parts of the brain stem. Williams and Wilkins Co, BaltimoreGoogle Scholar
  86. 86.
    Korsching S (1986) The role of nerve growth factor in the CNS. Trends Neurosci 101/102: 570–574Google Scholar
  87. 87.
    Korshing S, Thoenen H (1983) Nerve Growth Factor in sympathetic ganglia and corresponding target organs of the rat: correlation with density of sympathetic innervation. Proc Natl Acad Sci USA 80: 3513–3516Google Scholar
  88. 88.
    Korshing S, Heumann R, Thoenen M, Hefti F (1986) Cholinergic denervation of rat hippocampus by fimbriae transection leads to a transient accumulation of nerve growth factor (NGF) without changes in mRNA NGF contents. Neurosci Lett 66: 175–180Google Scholar
  89. 89.
    Ledeen R (1985) Gangliosides of the neurons. Trends Neurosci 86: 169–174Google Scholar
  90. 90.
    Leon A, Benvegnú D, Dal Toso R, Presti D, Facci L, Giorgi O, Toffano G (1984) Dorsal root ganglia and nerve growth factor: a model for understanding the mechanism of GM 1 effects on neuronal repair. J Neurosci Res 12: 277–287PubMedGoogle Scholar
  91. 91.
    Levi-Montalcini R (1982) Developmental neurobiology and the natural history of Nerve Growth Factor. Ann Rev Neurosci 5: 341–361PubMedGoogle Scholar
  92. 92.
    Levi-Montalcini R, Hamburger V (1951) Selective growth-stimulating effects of mouse sarcoma on the sensory and sympathetic system of the chick embryo. J Exp Zool 116: 321–362PubMedGoogle Scholar
  93. 93.
    Levi-Montalcini R, Hamburger V (1953) A diffusible agent of mouse sarcoma producing hyperplasia of sympathetic ganglia and hyperneurotization of the chick embryo. J Exp Zool 123: 233–288Google Scholar
  94. 94.
    Levi-Montalcini R, Angeletti PU (1968) Nerve Growth Factor. Physiol Rev 48: 535–569Google Scholar
  95. 95.
    Levi-Montalcini R, Calissano P (1986) Nerve Growth Factor as a paradigm of other polypeptide growth factors. Trends Neurosci 100: 473–477Google Scholar
  96. 96.
    Lewis ME, Lakshmanan D, Nagaiah K, MacDonnel PC, Guroff G (1978) Nerve Growth Factor increases activity of ornithine decarboxylase. Proc Natl Acad Sci USA 75: 1021–1023PubMedGoogle Scholar
  97. 97.
    Lindsay RM (1979) Adult rat brain astrocytes support survival of both NGFdependent and NGF-insensitive neurons. Nature 282: 80–82PubMedGoogle Scholar
  98. 98.
    Liu C-N, Chambers WW (1958) Intraspinal sprouting of dorsal root axons. AMA Arch Neurol Psychiat 79: 46–61Google Scholar
  99. 99.
    Longo FM, Selak I, Zovickian J, Manthorpe M, Varon S, U H-S (1984) Neuronotrophic activities in cerebrospinal fluid of head trauma patients. Exp Neurol 84: 207–218PubMedGoogle Scholar
  100. 100.
    Magistretti PJ, Manthorpe M, Bloom FE, Varon S (1983) Functional receptors for vasointestinal polypeptide in cultured astroglia from neonatal rat brain. Reg Peptides 6: 71–80Google Scholar
  101. 101.
    Manthorpe M, Engvall E, Rouslahti E, Longo FM, Davis GE, Varon S (1983a) Laminin promotes neuritic regeneration from cultured peripheral and central neurons. J Cell Biol 97: 1882–1890Google Scholar
  102. 102.
    Manthorpe M, Nieto-Sampedro M, Skaper SD, Lewis ER, Barbin G, Longo FM, Cotman CW, Varon S (1983b) Neuronotrophic activity in brain wounds of the developing rat. Correlation with implant survival in the wound cavity. Brain Res 267: 47–56Google Scholar
  103. 103.
    Manthorpe M, Varon S (1986) Regulation of neuronal survival and neuronal growth in the avian ciliary ganglion by trophic factors. In: Guroff G (ed) Growth and maturation factors, vol 3. John Wiley and Sons, New York (in press)Google Scholar
  104. 104.
    Marton LJ, Heby O, Levin VA, Lubich WP, Crafts DC, Wilson CB (1976) The relationship of polyamines in cerebrospinal fluid to the presence of central nervous system tumors. Cancer Res 36: 937–977Google Scholar
  105. 105.
    Michenfelder JD, Theye RA (1973) Cerebral protection by thiopental during hypoxia. Anaesthesiology 39: 510–517Google Scholar
  106. 106.
    Mobely WC, Rutkowski LJ, Temekoon GI, Johnston MU (1986) Nerve Growth Factor increases choline acetyltransferase in developing basal forebrain neurons. Mol Brain Res 1: 53–62Google Scholar
  107. 107.
    Morrison RS, deVellis J (1981) Growth of purified astrocytes in chronically defined medium. Proc Natl Acad Sci USA 78: 7205–7209PubMedGoogle Scholar
  108. 108.
    Needels DL, Nieto-Sampedro M, Cotman CW (1986) Induction of a neuritepromoting factor in rat brain following injury or deafferentation. Neuroscience 18: 517–526PubMedGoogle Scholar
  109. 109.
    Nicholson C (1980) Measurements of extracellular ions in the brain. Trends Neurosci 215–218Google Scholar
  110. 110.
    Nieto-Sampedro M, Lewis ER, Cotman CW, Manthorpe M, Skaper SD, Barbin G, Longo FM, Varon S (1982) Brain injury causes a time-dependent increase in neuronotrophic activity at the lesion site. Science 217: 860–861PubMedGoogle Scholar
  111. 111.
    Nilsson J, vonEuler AM, Dalsgaard CJ (1985) Stimulation of connective tissue cell growth by substance P and substance K. Nature (London) 315: 61–63Google Scholar
  112. 112.
    Noble M, Fok-Seang J, Cohen J (1984) Glia are a unique substrate for the in vitro growth of central nervous system neurons. J Neurosci 4: 1892–1904PubMedGoogle Scholar
  113. 113.
    Nyakas C, Veldhuis DH, DeWied D (1985) Beneficial effect of chronic treatment with Org2766 and a-MSH on impaired reversal learning of rats with bilateral lesions of parafascicular area. Brain Res Bull 15: 257–265PubMedGoogle Scholar
  114. 114.
    Nygren LG, Olson L, Seiger A (1971) Regeneration of monoamine containing axons in the developing and adult spinal cord of the rat following intraspinal 6-OH-dopamine injections or transections. Histochemie 28: 1–15PubMedGoogle Scholar
  115. 115.
    Oderfeld-Novak B, Wojcik M, Ulas J, Potempska A (1984) Effects of chronic ganglioside treatment on recovery processes in hippocampus after brain lesion in rats. In: Rapport MM, Glorio A (eds) Gangliosides in neurological and neuromuscular function, development and repair. Raven Press, New York, pp 85–95Google Scholar
  116. 116.
    O’Keefe E, Cuatrecasas P (1977) Persistence of exogenous inserted gangli-oside GM 1 on the cell surface of cultured cells. Life Sci 21: 1649–1653PubMedGoogle Scholar
  117. 117.
    Olson L, Malmfors T (1970) Growth characteristics of adrenergic nerves in adult rats. Fluorescence histochemistry and 3 H-noradrenaline uptake studies using tissue transplants to the anterior chamber of the eye. Acta Physiol Scand [Suppl] 348: 1–112Google Scholar
  118. 118.
    Olson L, Seiger A (1972) Early prenatal ontogeny of central monoamine neurons in the rat: fluorescence histochemical observations. Z Anat Entwickl Gesch 137: 301–316Google Scholar
  119. 119.
    Olson L (1985) On the use of transplants to counteract the symptoms of Parkinson disease: background, experimental models and possible clinical applications. In: Cotman CW (ed) Synaptic plasticity and remodelling. Guilford Press, New York, pp 485–505Google Scholar
  120. 120.
    Purves D, Lichtman JW (1985) Principles of neuronal development. Sinauer Ass Inc, SunderlandGoogle Scholar
  121. 121.
    Raisman G, Field PM (1973) A quantitative investigation of the development of collateral reinnervation after partial deafferentation of the septal nuclei. Brain Res 50: 241–264PubMedGoogle Scholar
  122. 122.
    Raizada MK (1983) Localization of insulin-like immunoreactivity in the neurons from primary cultures of rat brain. Exp Cell Res 143: 351–359PubMedGoogle Scholar
  123. 123.
    Ramon y Cajal S (1954) Neuronal theory or reticular theory?, Objective evidence of the anatomical unit of nerve cells (1908). In: Purkiss MU, Fox CA (eds) Consejo Superior de Investigaciones Cientifica, Inst S Ramon y Cajal, MadridGoogle Scholar
  124. 124.
    Ramon y Cajal S (1928) Degeneration and regeneration in the nervous system. Oxford University Press, LondonGoogle Scholar
  125. 125.
    Rapport MM, Gorio A (eds) Gangliosides in neurological and neuromuscular function, development and repair. Raven Press, New YorkGoogle Scholar
  126. 126.
    Reh T, Kalil K (1981) Development of the pyramidal tract in the hamster. I. A light microscope study. J Comp Neurol 200: 55–67PubMedGoogle Scholar
  127. 127.
    Reims S (1965) Contribution to the problem of the regeneration of nerve fibres in the central nervous system after operative damage in the early postnatal period. Acta Anat 60: 165–180Google Scholar
  128. 128.
    Rogers LR, Lotourneau PC, Palm SL, McCarthy J, Furcht LT (1983) Neurite extension by peripheral and central nervous system neurons in response to substratum-bound fibronectin and laminin. Dev Biol 98: 212–220PubMedGoogle Scholar
  129. 129.
    Rosengurt E, Sinnet-Smith J (1983) Bombesin stimulation of DNA synthesis and division in cultures of Swiss 3T3 cells. Proc Natl Acad Sci USA 80: 2936–2940Google Scholar
  130. 130.
    Rothman SM (1983) Synaptic activity mediates death of hypoxic neurons. Science 220: 536–537PubMedGoogle Scholar
  131. 131.
    Sabel BA, Slavin MD, Stein D (1984) GM 1 ganglioside treatment facilitates behavioral recovery from bilateral brain damage. Science 225: 340–342PubMedGoogle Scholar
  132. 132.
    Saji M, Reis DJ (1987) Delayed transneuronal death of substantia nigra neurons prevented by y-aminobutyric acid agonist. Science 235: 66–69PubMedGoogle Scholar
  133. 133.
    Sanes JR, Marshall LM, McMahan UJ (1980) Reinnervation of skeletal muscle: restoration of the normal synaptic pattern. In: Jewett DL, McCarrol HR (eds) Nerve repair and regeneration: its clinical and experimental basis. Mosby, St Louis, pp 130–138Google Scholar
  134. 134.
    Sapolski RM (1985) A mechanism for glucocorticoid toxicity in the hippocampus increased neuronal vulnerability to metabolic insults. J Neurosci 5: 1228–1232Google Scholar
  135. 135.
    Sara VR, Hall K, Mishaki M, Fryklund L, Christensen N, Wetterberg L (1983) Ontogenesis of somatomedin and insulin receptor in human fetus. J Clin Invest 71: 1084–1094PubMedGoogle Scholar
  136. 136.
    Savage CR Jr, Inagami T, Cohen S (1972) The primary structure of epidermal growth factor. J Biol Chem 247: 7612–7621PubMedGoogle Scholar
  137. 137.
    Scalabrino G, Ferioli M (1984) Polyamines in mammalian ageing: an oncological problem, too? A review. Mech Ageing Develop 26: 149–164Google Scholar
  138. 138.
    Schmidt RH, Björklund A, Stenevi U (1981) Intracerebral grafting of dissociated CNS tissue suspensions: a new approach for neuronal transplantion to deep brain sites. Brain Res 218: 347–356PubMedGoogle Scholar
  139. 139.
    Schmidt RH, Ingvar M, Lindvall O, Stenevi U, Björklund A (1982) Functional activity of substantia nigra grafts reinnervating the striatum: neurotransmitter metabolism and 14C-2-deoxi-D-glucose autoradiography. J Neurochem 38: 737–748PubMedGoogle Scholar
  140. 140.
    Schneider GE, Jhavary SR (1974) Neuroanatomical correlates of spared or altered functions after brain lesions in the newborn hamster. In: Stein SD, Rosen JJ, Butters N (eds) Plasticity and recovery of function in the central nervous system. Academic Press, New York, pp 65–110Google Scholar
  141. 141.
    Schwartz M, Spirman N (1982) Sprouting from chicken embryo dorsal root ganglia induced by nerve growth factor is specifically inhibited by affinity-purified antiganglioside antibody. Proc Natl Acad Sci USA 79: 6080–6083PubMedGoogle Scholar
  142. 142.
    Schwartzberg DG, Nakane PK (1982) Ontogenesis of adrenocorticotropinrelated peptide determinants in the hypothalamus and pituitary gland of the rat. Endocrinology 110: 855–864PubMedGoogle Scholar
  143. 143.
    Seiger A, Olson L (1973) Late prenatal ontogeny of central monoamine neurons in the rat: fluorescence histochemical observations. 2. Anat Entwickl Gesch 140: 281–318Google Scholar
  144. 144.
    Seiler N (1981) Polyamine metabolism and function in the brain. Neurochem Int 3: 95–110PubMedGoogle Scholar
  145. 145.
    Seiler N, Lamberty U (1975) Interrelations between polyamines and nucleic acids: changes of polyamine and nucleic acid concentrations in the developing rat brain. J Neurochem 24: 5–13PubMedGoogle Scholar
  146. 146.
    Seiler N, Schwab ME (1984) Specific retrograde transport of nerve growth factor (NGF) from neocortex to nucleus basalis in the rat. Brain Res 300: 33–39PubMedGoogle Scholar
  147. 147.
    Selak I, Skaper SD, Varon S (1983) Age-dependent requirements of sympathetic neurons in serum-free culture. Dev Brain Res 7: 171–179Google Scholar
  148. 148.
    Selak I, Skaper SD, Varon S (1985) Pyruvate partecipation in the low molecular weight trophic activity for CNS neurons in glia-contained media. J Neurosci 5: 23–28PubMedGoogle Scholar
  149. 149.
    Shaw GG (1979) The polyamines in the central nervous system. Biochem Pharmacol 28: 1–6PubMedGoogle Scholar
  150. 150.
    Shelton DL, Reichardt L (1986) Studies on the expression of the nerve growth factor (NGF) gene in the central nervous system: level and regional distribution of NGF mRNA suggest that NGF functions as trophic factor for several distinct populations of neurons. Proc Natl Acad Sci USA 83: 2714–2718PubMedGoogle Scholar
  151. 151.
    Skaper SD, Selak I, Varon S (1983) Serum and substratum-dependent modulation of neuritic growth. J Neurosci Res 9: 359–369PubMedGoogle Scholar
  152. 152.
    Skaper SD, Katoh-Semba R, Varon S (1985) GM 1 ganglioside accelerates neurite outgrowth from primary peripheral and central neurons under selected culture conditions. Dev Brain Res 23: 19–26Google Scholar
  153. 153.
    Skaper SD, Varon S (1986) Age-dependent control of dorsal root ganglion neuron survival by macromolecular and low-molecular weight trophic agents and substratum-bound laminins. Dev Brain Res 24: 39–46Google Scholar
  154. 154.
    So KF, Schneider GE (1976) Abnormal recrossing of retinotectal projections after early lesion in Syrian hamsters: a critical-age effect. Anat Rec 184: 535–536Google Scholar
  155. 155.
    Steward O (1982) Assessing the functional significance of lesion-induced neuronal plasticity. Int Rev Neurobiol 23: 197–253PubMedGoogle Scholar
  156. 156.
    Thoenen H, Barde YA (1980) Physiology of Nerve Growth Factor. Physiol Rev 60: 1284–1335PubMedGoogle Scholar
  157. 157.
    Thompson W (1983) Synapse elimination in neonatal muscle is sensitive to pattern of muscle use. Nature 302: 612–614Google Scholar
  158. 158.
    Toffano G, Savoini G, Moroni F, Lombardi G, Calza L, Agnati LF (1983) GM 1 ganglioside stimulates the regeneration of dopaminergic neurons in the central nervous system. Brain Res 261: 163–166PubMedGoogle Scholar
  159. 159.
    Ushiro H, Cohen S (1980) Identification of phosphotyrosine as a product of Epidermal Growth Factor-activated protein kinase in A-431 cell membrane. J Biol Chem 255: 8363–8365PubMedGoogle Scholar
  160. 160.
    Van Schravendijk CFH, Hooghe-Peters EL, de Meyts P, Pipelers DJ (1984) Identification and characterization of insulin receptors on foetal-mouse brain cortical cells. Biochem J 220: 165–172PubMedGoogle Scholar
  161. 161.
    Varon S (1985) Factors promoting the growth of the nervous system. Discussions in Neurosciences, voltGoogle Scholar
  162. 162.
    Varon S, Adler R (1981) Trophic and specific factors directed to neuronal cells. Adv Cell Neurobiol 2: 115–163Google Scholar
  163. 163.
    Varon S, Skaper SD, Barbin G, Selak I, Manthorpe M (1984) Low molecular weight agents support survival of cultured neurons from the CNS. J Neurosci 4: 654–658PubMedGoogle Scholar
  164. 164.
    Varon S, Manthorpe M (1985) In vitro models for neuroplasticity and repair. In: Bignami A, Bloom FE, Bolis CL, Adeloye A (eds) Central nervous system plasticity and repair. Raven Press, New York, pp 13–23Google Scholar
  165. 165.
    Veraa RP, Grafstein B (1981) Cellular mechanisms for recovery from nervous system injury: a conference report. Exp Neurol 38: 490–497Google Scholar
  166. 166.
    Vizi ES (1984) Non-synaptic interactions between neurons: modulation of chemical transmission. John Wiley, New YorkGoogle Scholar
  167. 167.
    Walicke P, Varon S, Manthorpe M, Purification of a human red blood cell protein supporting the survival of cultured CNS neurons and its identification as a catalase (manuscript in preparation)Google Scholar
  168. 168.
    Waterfield MD, Scrace GT, Whittle N, Stroobant P, Johnsson A, Wasteson A, Westermark B, Heldin CH, Huang JS, Deuel TF (1983) Platelet-derived growth factor is structurally related to the putative transforming protein p28-sis of simian sarcoma virus. Nature (London) 304: 31–39Google Scholar
  169. 169.
    Watson SJ, Richard III CW, Barchas JD (1978) Adrenocorticotropin in rat brain: immunocytochemical localization in cells and axons. Science 200: 1180–1182PubMedGoogle Scholar
  170. 170.
    Weinberg EL, Spencer PS (1979) Studies on the control of myelinogenesis. 3. Signalling of oligodendrocyte myelination by regenerating peripheral axons. Brain Res 162: 273–279PubMedGoogle Scholar
  171. 171.
    Williams PL, Warwick R (eds) Gray’s Anatomy. 36th ed, Longman, London 1980Google Scholar
  172. 172.
    Windle WF (1956) Regeneration of axons in the vertebrate central nervous system. Physiol Rev 36: 427–440PubMedGoogle Scholar
  173. 173.
    Whittemore SR, Ebendal T, Larkfors L, Olson L, Seiger A, Stromberg I, Persson H (1986) Developmental and regional expression of 13-nerve growth factor messenger RNA and protein in the central nervous system. Proc Natl Acad Sci USA 83: 817–821PubMedGoogle Scholar
  174. 174.
    Yankner BA, Shooter EM (1982) The biology and mechanism of action of Nerve Growth Factor. Ann Rev Biochem 51: 845–868PubMedGoogle Scholar
  175. 175.
    Zini I, Zoli M, Agnati LF, Fuxe K, Merlo Pich E, Davalli P, Corti A, Gavioli G, Toffano G (1986) Studies on the involvement of polyamines for the trophic actions of the ganglioside GM 1 in mechanically and 6-hydroxydopamine lesioned rats. Evidence for a permissive role of putrescine. In: Tettamanti G, Ledeen RW, Sandhoff K, Nagai Y, Toffano G (eds) Gangliosides and neuronal plasticity. Springer, New York Heidelberg, Liviana Press, Padova, pp 381–396Google Scholar

Copyright information

© Springer-Verlag/Wien 1988

Authors and Affiliations

  • L. F. Agnati
    • 5
  • I. Zini
    • 1
  • M. Zoli
    • 1
  • K. Fuxe
    • 2
  • E. Merlo Pich
    • 1
  • R. Grimaldi
    • 1
  • G. Toffano
    • 3
  • M. Goldstein
    • 4
  1. 1.Department of Human PhysiologyUniversity of ModenaItaly
  2. 2.Department of HistologyKarolinska InstituteStockholmSweden
  3. 3.Fidia Research LaboratoriesAbano TermeItaly
  4. 4.Department of PsychiatryNew York University School of MedicineUSA
  5. 5.Istituto di Fisiologia UmanaUniversitá di ModenaModenaItaly

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