Hostname: page-component-76fb5796d-zzh7m Total loading time: 0 Render date: 2024-04-26T15:18:43.486Z Has data issue: false hasContentIssue false
  • English
  • Français

Canadian Association of Neuroscience Review: Axonal Regeneration in the Peripheral and Central Nervous Systems – Current Issues and Advances

Published online by Cambridge University Press:  16 February 2016

Keith Fenrich  and
Tessa Gordon
Keith Fenrich
Affiliation:
Centre for Neuroscience, Division of Physical Medicine and Rehabilitation, University of Alberta, Edmonton, AB, Canada
Tessa Gordon*
Affiliation:
Centre for Neuroscience, Division of Physical Medicine and Rehabilitation, University of Alberta, Edmonton, AB, Canada
*
Centre for Neuroscience, Division of Physical Medicine and Rehabilitation, University of Alberta, Edmonton, AB, Canada T6G 2S2
Rights & Permissions [Opens in a new window]

Abstract

Core share and HTML view are not available for this content. However, as you have access to this content, a full PDF is available via the ‘Save PDF’ action button.

Injured nerves regenerate their axons in the peripheral (PNS) but not the central nervous system (CNS). The contrasting capacities have been attributed to the growth permissive Schwann cells in the PNS and the growth inhibitory environment of the oligodendrocytes in the CNS. In the current review, we first contrast the robust regenerative response of injured PNS neurons with the weak response of the CNS neurons, and the capacity of Schwann cells and not the oligodendrocytes to support axonal regeneration. We then consider the factors that limit axonal regeneration in both the PNS and CNS. Limiting factors in the PNS include slow regeneration of axons across the injury site, progressive decline in the regenerative capacity of axotomized neurons (chronic axotomy) and progressive failure of denervated Schwann cells to support axonal regeneration (chronic denervation). In the CNS on the other hand, it is the poor regenerative response of neurons, the inhibitory proteins that are expressed by oligodendrocytes and act via a common receptor on CNS neurons, and the formation of the glial scar that prevent axonal regeneration in the CNS. Strategies to overcome these limitations in the PNS are considered in detail and contrasted with strategies in the CNS.

Type
Review Article
Information
Canadian Journal of Neurological Sciences , Volume 31 , Issue 2 , May 2004 , pp. 142 - 156
Copyright
Copyright © The Canadian Journal of Neurological 2004

References

1.Fu, SY, Gordon, T. The cellular and molecular basis of peripheral nerve regeneration. Mol Neurobiol 1997; 14:67–116.CrossRefGoogle ScholarPubMed
2.Boyd, JG, Gordon, T. Neurotrophic factors and their receptors in axonal regeneration and functional recovery after peripheral nerve injury. Mol Neurobiol 2003; 27:277–324.CrossRefGoogle ScholarPubMed
3.Kline, DG, Hudson, AR. Nerve Injuries: Operative Results for Major Nerve Injuries, Entrapments and Tumors. Philadelphia: 1995.Google Scholar
4.Kury, P, Stoll, G, Muller, HW. Molecular mechanisms of cellular interactions in peripheral nerve regeneration. Curr Opin Neurol 2001; 14:635-639.CrossRefGoogle ScholarPubMed
5.Sulaiman, OAR, Boyd, JG, Gordon, T. Regeneration in the peripheral system of mammals. Neuroglia 2003; In press.Google Scholar
6.Fawcett, J. Repair of spinal cord injuries: where are we, where are we going? Spinal Cord 2002; 40:615–623.Google ScholarPubMed
7.Bunge, MB. Bridging areas of injury in the spinal cord. Neuroscientist 2001; 7:325–339.CrossRefGoogle ScholarPubMed
8.Horner, PJ, Gage, FH. Regenerating the damaged central nervous system. Nature 2000; 407:963–970.CrossRefGoogle ScholarPubMed
9.Fouad, K, Dietz, V, Schwab, ME. Improving axonal growth and functional recovery after experimental spinal cord injury by neutralizing myelin associated inhibitors. Brain Res Brain Res Rev 2001; 36:204–212.CrossRefGoogle ScholarPubMed
10.Edgerton, VR, Roy, RR. Paralysis recovery in humans and model systems. Curr Opin Neurobiol 2002; 12:658–667.CrossRefGoogle ScholarPubMed
11.David, S, Lacroix, S. Molecular approaches to spinal cord repair. Ann Rev Neurosci 2003.CrossRefGoogle ScholarPubMed
12.Klusman, I, Schwab, ME. Axonal regeneration in the central nervous system of mammals. Neuroglia 2003; In press.Google Scholar
13.Goldberg, JL, Barres, BA. The relationship between neuronal survival and regeneration. Ann Rev Neurosci 2000; 23:579–612.Google ScholarPubMed
14.Steward, O, Zheng, B, Tessier-Lavigne, M. False resurrections: distinguishing regenerated from spared axons in the injured central nervous system. J Comp Neurol 2003; 459:1–8.CrossRefGoogle ScholarPubMed
15.Selzer, ME. Promotion of axonal regeneration in the injured CNS. Lancet Neurol 2003; 2:157–166.CrossRefGoogle ScholarPubMed
16.Waller, A. Experiments on the section of the glossopharyngeal and hypoglossal nerves of the frog, and observations of the alterations produced thereby in the structure of their primitive fibers. Phil Transact Royal Soc London 1850; 140:423–429.Google Scholar
17.Cajal Ramon, Y. Degeneration and Regeneration of the Nervous System. New York: Hafner Publishing Co, 1959.Google Scholar
18.Stoll, G, Jander, S, Myers, RR. Degeneration and regeneration of the peripheral nervous system: from Augustus Waller’s observations to neuroinflammation. J Peripher Nerv Syst 2002; 7:13–27.CrossRefGoogle ScholarPubMed
19.Vrbova, G, Gordon, T, Jones, R. Nerve-Muscle Interaction. 2nd ed; London: Chapman and Hall, 1995.Google Scholar
20.Stoll, G, et al. Wallerian degeneration in the peripheral nervous system: participation of both Schwann cells and macrophages in myelin degradation. J Neurocytol 1989; 18:671–683.CrossRefGoogle ScholarPubMed
21.Schlaepfer, WW, Bunge, RP. Effects of calcium ion concentration on the degeneration of amputated axons in tissue culture. J Cell Biol 1973; 59:456–470.CrossRefGoogle ScholarPubMed
22.George, EB, Glass, JD, Griffin, JW. Axotomy-induced axonal degeneration is mediated by calcium influx through ion-specific channels. J Neuroscience 1995; 15:6445–6452.CrossRefGoogle ScholarPubMed
23.LeBlanc, AC, Poduslo, JF. Axonal modulation of myelin gene expression in the peripheral nerve. J Neurosci Res 1990; 26:317–326.CrossRefGoogle ScholarPubMed
24.Cohan, CS. Depolarization-induced changes in neurite elongation and intracellular Ca2+ in isolated Helisoma neurons. J Neurobiol 1992; 23:983–996.Google ScholarPubMed
25.Hall, SM. The biology of chronically denervated Schwann cells. Ann NYAcad Sci 1999; 883:215–233.CrossRefGoogle ScholarPubMed
26.Liu, HM, Yang, LH, Yang, YJ. Schwann cell properties: 3. C-fos expression, bFGF production, phagocytosis and proliferation during Wallerian degeneration. J Neuropathol Exp Neurol 1995; 54:487–496.CrossRefGoogle ScholarPubMed
27.Hirata, K, Kawabuchi, M. Myelin phagocytosis by macrophages and nonmacrophages during Wallerian degeneration. Microsc Res Tech 2002; 57:541–547.CrossRefGoogle ScholarPubMed
28.Anton, ES, et al. Nerve growth factor and its low-affinity receptor promote Schwann cell migration. Proc Natl Acad Sci USA 1994; 91:2795–2799.CrossRefGoogle ScholarPubMed
29.Bruck, W. The role of macrophages in Wallerian degeneration. Brain Pathol 1997; 7:741–752.CrossRefGoogle ScholarPubMed
30.Avellino, AM, et al. Differential macrophage responses in the peripheral and central nervous system during wallerian degeneration of axons. Exp Neurol 1995; 136:183–198.CrossRefGoogle ScholarPubMed
31.Perry, VH, Brown, MC, Gordon, S. The macrophage response to central and peripheral nerve injury. A possible role for macrophages in regeneration. J Exp Med 1987; 165:1218–1223.CrossRefGoogle ScholarPubMed
32.Reichert, F, Saada, A, Rotshenker, S. Peripheral nerve injury induces Schwann cells to express two macrophage phenotypes: phagocytosis and the galactose-specific lectin MAC-2. J Neuroscience 1994; 14:3231–3245.CrossRefGoogle ScholarPubMed
33.Tofaris, GK, et al. Denervated Schwann cells attract macrophages by secretion of leukemia inhibitory factor (LIF) and monocyte chemoattractant protein-1 in a process regulated by interleukin-6 and LIF. J Neuroscience 2002; 22:6696–6703.CrossRefGoogle Scholar
34.Liefner, M, et al. The role of TNF-alpha during Wallerian degeneration. J Neuroimmunol 2000; 108:147–152.CrossRefGoogle ScholarPubMed
35.Vrbova, G, Gordon, T, Jones, R. Nerve-Muscle Interaction. 2nd ed. London: Chapman and Hall, 1995.Google Scholar
36.Martini, R. Expression and functional roles of neural cell surface molecules and extracellular matrix components during development and regeneration of peripheral nerves. J Neurocytol 1994; 23:1–28.CrossRefGoogle ScholarPubMed
37.Tang, S, et al. Soluble myelin-associated glycoprotein (MAG) found in vivo inhibits axonal regeneration. Mol Cell Neurosci 1997; 9:333–346.Google ScholarPubMed
38.Filbin, MT. The Muddle with MAG. Mol Cell Neurosci 1996; 8:84–92.Google ScholarPubMed
39.Filbin, MT. Myelin-associated glycoprotein: a role in myelination and in the inhibition of axonal regeneration? Curr Opin Neurobiol 1995; 5:588–595.CrossRefGoogle ScholarPubMed
40.Shamash, S, Reichert, F, Rotshenker, S. The cytokine network of Wallerian degeneration: tumor necrosis factor-alpha, interleukin-1alpha, and interleukin-1beta. J Neurosci 2002; 22:3052–3060.CrossRefGoogle ScholarPubMed
41.Gillen, C, Jander, S, Stoll, G. Sequential expression of mRNA for proinflammatory cytokines and interleukin-10 in the rat peripheral nervous system: comparison between immune-mediated demyelination and Wallerian degeneration. J Neurosci Res 1998; 51:489–496.3.0.CO;2-8>CrossRefGoogle ScholarPubMed
42.Stoll, G, et al. Tumor necrosis factor-alpha in immune-mediated demyelination and Wallerian degeneration of the rat peripheral nervous system. J Neuroimmunol 1993; 45:175–182.CrossRefGoogle ScholarPubMed
43.Oppenhheim, JJ, Feldman, M. Introduction to the role of cytokines in innate and defense and adaptive immunity. In: Oppenheim, JJ, Feldman, M, (Eds). Cytokines Reference. New York: Academic, 2001;3–20.Google Scholar
44.Gordon, T. Dependence of peripheral nerves on their target organs. In Burnstock, G, Vrbova, G, O’Brien, R (Eds). Somatic and Autonomic Nerve-Muscle Interactions. New York, NY: Elsevier Science Publishers, 1983;289–325.Google Scholar
45.Kreutzberg, GW. Principles of neuronal regeneration. Acta Neurochir Suppl 1996; 66:103–106.Google ScholarPubMed
46.Kreutzberg, GW. Reaction of the cell body to axonal damage. In: Waxman, SG, Kocsis, JD, Stys, PK, (Eds). The Axon. New York, Oxford: Oxford University Press, 1995;355–374.CrossRefGoogle Scholar
47.Bulsara, KR, et al. A new millenium for spinal cord regeneration: growth-associated genes. Spine 2002; 27:1946–1949.Google ScholarPubMed
48.Bomze, HM, et al. Spinal axon regeneration evoked by replacing two growth cone proteins in adult neurons. Nat Neurosci 2001; 4:38–43.CrossRefGoogle ScholarPubMed
49.Strittmatter, SM, Igarashi, M, Fishman, MC. GAP-43 amino terminal peptides modulate growth cone morphology and neurite outgrowth. J Neuroscience 1994; 14:5503–5513.CrossRefGoogle ScholarPubMed
50.Igarashi, M, et al. Ligand-induced growth cone collapse: amplification and blockade by variant GAP-43 peptides. J Neuroscience 1995; 15:5660–5667.CrossRefGoogle ScholarPubMed
51.Tetzlaff, W, et al. Retrograde changes in transglutaminase activity after peripheral nerve injuries. Brain Res 1988; 445:142–146.CrossRefGoogle ScholarPubMed
52.Tetzlaff, W, et al. Response of facial and rubrospinal neurons to axotomy: changes in mRNA expression for cytoskeletal proteins and GAP-43. J Neurosci 1991; 11:2528–2544.CrossRefGoogle ScholarPubMed
53.Gordon, T, et al. Axotomy-induced changes in rabbit hindlimb nerves and the effects of chronic electrical stimulation. J Neurosci 1991; 11:2157–2169.Google ScholarPubMed
54.Tetzlaff, W, et al. Reductions in motoneuronal neurofilament synthesis by successive axotomies: a possible explanation for the conditioning lesion effect on axon regeneration. Exp Neurol 1996; 139:95–106.CrossRefGoogle ScholarPubMed
55.Rahmatullah, M, et al. Synergistic regulation of Schwann cell proliferation by heregulin and forskolin. Mol Cell Biol 1998; 18:6245–6252.CrossRefGoogle ScholarPubMed
56.Carroll, SL, et al. Expression of neuregulins and their putative receptors, ErbB2 and ErbB3, is induced during Wallerian degeneration. J Neurosci 1997; 17:1642–1659.CrossRefGoogle ScholarPubMed
57.Sulaiman, O, Boyd, JG, Gordon, T. Regeneration in the peripheral nervous system of mammals. In Kettermann, H, Ransom, B, (Eds). Neuroglia. 2nd ed. 2003 (In press).Google Scholar
58.Ide, C. Peripheral nerve regeneration. Neurosci Res 1996; 25:101–121.CrossRefGoogle ScholarPubMed
59.Guenard, V, et al. Onion bulb cells in mice deficient for myelin genes share molecular properties with immature, differentiated nonmyelinating, and denervated Schwann cells. Glia 1996; 18:27–38.Google ScholarPubMed
60.Mirsky, R, Jessen, KR. The neurobiology of Schwann cells. Brain Pathol 1999; 9:293–311.Google ScholarPubMed
61.Scherer, SS, Salzer, JL. Axon-Schwann cell interactions during peripheral nerve degeneration and regeneration. Glial Cell Development: Basic Principles and Clinical Relevance 1996;169–196.Google Scholar
62.Scherer, SS, Arroyo, EJ. Recent progress on the molecular organization of myelinated axons. J Peripher Nerv Syst 2002; 7:1–12.CrossRefGoogle ScholarPubMed
63.Markus, A, Patel, TD, Snider, WD. Neurotrophic factors and axonal growth. Curr Opin Neurobiol 2002; 12:523–531.CrossRefGoogle ScholarPubMed
64.Funakoshi, H, et al. Differential expression of mRNAs for neurotrophins and their receptors after axotomy of the sciatic nerve. J Cell Biol 1993; 123:455–465.CrossRefGoogle ScholarPubMed
65.Hoke, A, et al. A decline in glial cell-line-derived neurotrophic factor expression is associated with impaired regeneration after long-term Schwann cell denervation. Exp Neurol 2002; 173:77–85.CrossRefGoogle ScholarPubMed
66.Ito, Y, et al. Differential temporal expression of mRNAs for ciliary neurotrophic factor (CNTF), leukemia inhibitory factor (LIF), interleukin-6 (IL-6), and their receptors (CNTFR alpha, LIFR beta, IL-6R alpha and gp130) in injured peripheral nerves. Brain Res 1998; 793:321–327.CrossRefGoogle Scholar
67.Meyer, M, et al. Enhanced synthesis of brain-derived neurotrophic factor in the lesioned peripheral nerve: different mechanisms are responsible for the regulation of BDNF and NGF mRNA. J Cell Biol 1992; 119:45–54.CrossRefGoogle ScholarPubMed
68.Naveilhan, P, ElShamy, WM, Ernfors, P. Differential regulation of mRNAs for GDNF and its receptors Ret and GDNFR alpha after sciatic nerve lesion in the mouse. Eur J Neurosci 1997; 9:1450–1460.Google ScholarPubMed
69.Seniuk, N, et al. Decreased synthesis of ciliary neurotrophic factor in degenerating peripheral nerves. Brain Res 1992; 572:300–302.CrossRefGoogle ScholarPubMed
70.Bolin, LM, et al. Interleukin-6 production by Schwann cells and induction in sciatic nerve injury. J Neurochem 1995; 64:850–858.Google ScholarPubMed
71.Griffin, JW, George, R, Ho, T. Macrophage systems in peripheral nerves. A review. J Neuropathol Exp Neurol 1993; 52:553–560.CrossRefGoogle ScholarPubMed
72.Araki, T, Nagarajan, R, Milbrandt, J. Identification of genes induced in peripheral nerve after injury. Expression profiling and novel gene discovery. J Biol Chem 2001; 276:34131–34141.CrossRefGoogle ScholarPubMed
73.George, R, Griffin, JW. Delayed macrophage responses and myelin clearance during Wallerian degeneration in the central nervous system: the dorsal radiculotomy model. Exp Neurol 1994; 129:225–236.CrossRefGoogle ScholarPubMed
74.Rapalino, O, et al. Implantation of stimulated homologous macrophages results in partial recovery of paraplegic rats. Nat Med 1998; 4:814–821.CrossRefGoogle ScholarPubMed
75.Stoll, G, Muller, HW. Nerve injury, axonal degeneration and neural regeneration: basic insights. Brain Pathol 1999; 9:313–325.Google ScholarPubMed
76.Bandtlow, CE, Schwab, ME. NI-35/250/nogo-a: a neurite growth inhibitor restricting structural plasticity and regeneration of nerve fibers in the adult vertebrate CNS. Glia 2000; 29:175–181.Google ScholarPubMed
77.Qiu, J, Cai, D, Filbin, MT. Glial inhibition of nerve regeneration in the mature mammalian CNS. Glia 2000; 29:166–174.3.0.CO;2-G>CrossRefGoogle ScholarPubMed
78.Filbin, MT. Myelin-associated inhibitors of axonal regeneration in the adult mammalian CNS. Nat Rev Neurosci 2003; 4:703–713.CrossRefGoogle ScholarPubMed
79.Mukhopadhyay, G, et al. A novel role for myelin-associated glycoprotein as an inhibitor of axonal regeneration. Neuron 1994; 13:757–767.CrossRefGoogle ScholarPubMed
80.Nakajima, K, Kohsaka, S. Microglia: activation and their significance in the central nervous system. J Biochem (Tokyo) 2001; 130:169–175.Google ScholarPubMed
81.Leskovar, A, et al. The macrophage in acute neural injury: changes in cell numbers over time and levels of cytokine production in mammalian central and peripheral nervous systems. J Exp Biol 2000; 203(12):1783–1795.CrossRefGoogle ScholarPubMed
82.Jander, S, Lausberg, F, Stoll, G. Differential recruitment of CD8+ macrophages during Wallerian degeneration in the peripheral and central nervous system. Brain Pathol 2001; 11:27–38.CrossRefGoogle ScholarPubMed
83.Bush, MS, et al. Expression of a developmentally regulated, phosphorylated isoform of microtubule-associated protein 1B in regenerating axons of the sciatic nerve. Neuroscience 1996; 73:553–563.CrossRefGoogle ScholarPubMed
84.Caroni, P, Aigner, L, Schneider, C. Intrinsic neuronal determinants locally regulate extrasynaptic and synaptic growth at the adult neuromuscular junction. J Cell Biol 1997; 136:679–692.CrossRefGoogle ScholarPubMed
85.Caroni, P. Intrinsic neuronal determinants that promote axonal sprouting and elongation. Bioessays 1997; 19:767–775.CrossRefGoogle ScholarPubMed
86.Caroni, P. Overexpression of growth-associated proteins in the neurons of adult transgenic mice. J Neurosci Methods 1997; 71:3–9.CrossRefGoogle ScholarPubMed
87.De la Monte, SM, et al. GAP-43 gene expression during development: persistence in a distinctive set of neurons in the mature central nervous system. Brain Res Dev Brain Res 1989; 46:161–168.CrossRefGoogle Scholar
88.Herdegen, T, Skene, P, Bahr, M. The c-Jun transcription factor-bipotential mediator of neuronal death, survival and regeneration. Trends Neurosci 1997; 20:227–231.CrossRefGoogle ScholarPubMed
89.Jacobson, RD, Virag, I, Skene, JH. A protein associated with axon growth, GAP-43, is widely distributed and developmentally regulated in rat CNS. J Neurosci 1986; 6:1843–1855.CrossRefGoogle ScholarPubMed
90.Simkowitz, P, Ellis, L, Pfenninger, KH. Membrane proteins of the nerve growth cone and their developmental regulation. J Neurosci 1989; 9:1004–1017.CrossRefGoogle ScholarPubMed
91.Skene, JH, et al. A protein induced during nerve growth (GAP-43) is a major component of growth-cone membranes. Science 1986; 233:783–786.CrossRefGoogle Scholar
92.Skene, JH. Axonal growth-associated proteins. Annu Rev Neurosci 1989; 12:127–156.CrossRefGoogle ScholarPubMed
93.Fernandes, KJ, et al. Influence of the axotomy to cell body distance in rat rubrospinal and spinal motoneurons: differential regulation of GAP-43, tubulins, and neurofilament-M. J Comp Neurol 1999; 414:495–510.3.0.CO;2-S>CrossRefGoogle ScholarPubMed
94.Hiebert, GW, et al. Immunological myelin disruption does not alter expression of regeneration-associated genes in intact or axotomized rubrospinal neurons. Exp Neurol 2000; 163:149–156.CrossRefGoogle ScholarPubMed
95.Kwon, BK, Tetzlaff, W. Spinal cord regeneration: from gene to transplants. Spine 2001; 26:13–22.CrossRefGoogle ScholarPubMed
96.Plunet, W, Kwon, BK, Tetzlaff, W. Promoting axonal regeneration in the central nervous system by enhancing the cell body response to axotomy. J Neurosci Res 2002; 68:1–6.CrossRefGoogle ScholarPubMed
97.Doster, SK, et al. Expression of the growth-associated protein GAP-43 in adult rat retinal ganglion cells following axon injury. Neuron 1991; 6:635–647.CrossRefGoogle ScholarPubMed
98.Benfey, M, Aguayo, AJ. Extensive elongation of axons from rat brain into peripheral nerve grafts. Nature 1982; 296:150–152.CrossRefGoogle ScholarPubMed
99.David, S, Aguayo, AJ. Axonal elongation into peripheral nervous system “bridges” after central nervous system injury in adult rats. Science 1981; 214:931–933.Google ScholarPubMed
100.Richardson, PM, McGuinness, UM, Aguayo, AJ. Axons from CNS neurons regenerate into PNS grafts. Nature 1980; 284:264–265.CrossRefGoogle ScholarPubMed
101.Vidal-Sanz, M, et al. Axonal regeneration and synapse formation in the superior colliculus by retinal ganglion cells in the adult rat. J Neurosci 1987; 7:2894–2909.CrossRefGoogle ScholarPubMed
102.So, KF, Aguayo, AJ. Lengthy regrowth of cut axons from ganglion cells after peripheral nerve transplantation into the retina of adult rats. Brain Res 1985; 328:349–354.CrossRefGoogle ScholarPubMed
103.Paino, CL, et al. Regrowth of axons in lesioned adult rat spinal cord: promotion by implants of cultured Schwann cells. J Neurocytol 1994; 23:433–452.Google ScholarPubMed
104.Savio, T, Schwab, ME. Lesioned corticospinal tract axons regenerate in myelin-free rat spinal cord. Proc Natl Acad Sci USA 1990; 87:4130–4133.CrossRefGoogle ScholarPubMed
105.Liu, Y, et al. Transplants of fibroblasts genetically modified to express BDNF promote regeneration of adult rat rubrospinal axons and recovery of forelimb function. J Neurosci 1999; 19:4370–4387.CrossRefGoogle ScholarPubMed
106.Tuszynski, MH, Mafong, E, Meyer, S. Central infusions of brain-derived neurotrophic factor and neurotrophin-4/5, but not nerve growth factor and neurotrophin-3, prevent loss of the cholinergic phenotype in injured adult motor neurons. Neuroscience 1996; 71:761–771.CrossRefGoogle Scholar
107.Weidner, N, et al. Nerve growth factor-hypersecreting Schwann cell grafts augment and guide spinal cord axonal growth and remyelinate central nervous system axons in a phenotypically appropriate manner that correlates with expression of L1. J Comp Neurol 1999; 413:495–506.3.0.CO;2-Z>CrossRefGoogle Scholar
108.Hiebert, GW, et al. Brain-derived neurotrophic factor applied to the motor cortex promotes sprouting of corticospinal fibers but not regeneration into a peripheral nerve transplant. J Neurosci Res 2002; 69:160–168.CrossRefGoogle Scholar
109.Mohajeri, MH, Figlewicz, DA, Bohn, MC. Intramuscular grafts of myoblasts genetically modified to secrete glial cell line-derived neurotrophic factor prevent motoneuron loss and disease progression in a mouse model of familial amyotrophic lateral sclerosis. Hum Gene Ther 1999; 10:1853–1866.Google Scholar
110.Tuszynski, MH, Gage, FH. Bridging grafts and transient nerve growth factor infusions promote long-term central nervous system neuronal rescue and partial functional recovery. Proc Natl Acad Sci U S A 1995; 92:4621–4625.CrossRefGoogle ScholarPubMed
111.Lu, P, Blesch, A, Tuszynski, MH. Neurotrophism without neurotropism: BDNF promotes survival but not growth of lesioned corticospinal neurons. J Comp Neurol 2001; 436:456–470.CrossRefGoogle Scholar
112.Caroni, P, Schwab, ME. Two membrane protein fractions from rat central myelin with inhibitory properties for neurite growth and fibroblast spreading. J Cell Biol 1988; 106:1281–1288.CrossRefGoogle ScholarPubMed
113.Chen, Y, Swanson, RA. Astrocytes and brain injury. J Cereb Blood Flow Metab 2003; 23:137–149.CrossRefGoogle ScholarPubMed
114.McKeon, RJ, et al. Reduction of neurite outgrowth in a model of glial scarring following CNS injury is correlated with the expression of inhibitory molecules on reactive astrocytes. J Neurosci 1991; 11:3398–3411.CrossRefGoogle Scholar
115.Jones, LL, Margolis, RU, Tuszynski, MH. The chondroitin sulfate proteoglycans neurocan, brevican, phosphacan, and versican are differentially regulated following spinal cord injury. Exp Neurol 2003; 182:399–411.CrossRefGoogle ScholarPubMed
116.Jakeman, LB, Reier, PJ. Axonal projections between fetal spinal cord transplants and the adult rat spinal cord: a neuroanatomical tracing study of local interactions. J Comp Neurol 1991; 307:311–334.CrossRefGoogle ScholarPubMed
117.Kruger, S, et al. Three morphologically distinct types of interface develop between adult host and fetal brain transplants: implications for scar formation in the adult central nervous system. J Comp Neurol 1986; 249:103–116.CrossRefGoogle ScholarPubMed
118.Rier, PJ, Stensass, LJ, Guth, L. The astrocytic scar as an impediment to regeneration in the CNS. In: Kao, CC, Burge, RP, Reter, PJ, (Eds). Spinal Cord Reconstruction. New York: Raven Press, 1983;163–195.Google Scholar
119.Rudge, JS, Silver, J. Inhibition of neurite outgrowth on astroglial scars in vitro. J Neurosci 1990; 10:3594–3603.Google ScholarPubMed
120.Bandtlow, CE, Zimmermann, DR. Proteoglycans in the developing brain: new conceptual insights for old proteins. Physiol Rev 2000; 80:1267–1290.Google ScholarPubMed
121.Davies, SJ, et al. Robust regeneration of adult sensory axons in degenerating white matter of the adult rat spinal cord. J Neurosci 1999; 19:5810–5822.Google ScholarPubMed
122.Fawcett, JW, Asher, RA. The glial scar and central nervous system repair. Brain Res Bull 1999; 49:377–391.CrossRefGoogle ScholarPubMed
123.Caroni, P, Schwab, ME. Antibody against myelin-associated inhibitor of neurite growth neutralizes nonpermissive substrate properties of CNS white matter. Neuron 1988; 1:85–96.CrossRefGoogle ScholarPubMed
124.Schnell, L, Schwab, ME. Axonal regeneration in the rat spinal cord produced by an antibody against myelin-associated neurite growth inhibitors. Nature 1990; 343:269–272.CrossRefGoogle ScholarPubMed
125.Bregman, BS, et al. Recovery from spinal cord injury mediated by antibodies to neurite growth inhibitors. Nature 1995; 378:498–501.CrossRefGoogle ScholarPubMed
126.Chen, MS, et al. Nogo-A is a myelin-associated neurite outgrowth inhibitor and an antigen for monoclonal antibody IN-1. Nature 2000; 403:434–439.CrossRefGoogle Scholar
127.GrandPre, T, et al. Identification of the Nogo inhibitor of axon regeneration as a Reticulon protein. Nature 2000; 403:439–444.CrossRefGoogle ScholarPubMed
128.Prinjha, R, et al. Inhibitor of neurite outgrowth in humans. Nature 2000; 403:383–384.CrossRefGoogle ScholarPubMed
129.Pot, C, et al. Nogo-A expressed in Schwann cells impairs axonal regeneration after peripheral nerve injury. J Cell Biol 2002; 159:29–35.CrossRefGoogle ScholarPubMed
130.Oertle, T, Schwab, ME. Nogo and its partners. Trends Cell Biol 2003; 13:187–194.CrossRefGoogle ScholarPubMed
131.Huber, AB, et al. Patterns of Nogo mRNA and protein expression in the developing and adult rat and after CNS lesions. J Neurosci 2002; 22:3553–3567.CrossRefGoogle ScholarPubMed
132.Hunt, D, Coffin, RS, Anderson, PN. The Nogo receptor, its ligands and axonal regeneration in the spinal cord; a review. J Neurocytol 2002; 31:93–120.Google ScholarPubMed
133.Fournier, AE, GrandPre, T, Strittmatter, SM. Identification of a receptor mediating Nogo-66 inhibition of axonal regeneration. Nature 2001; 409:341–346.CrossRefGoogle ScholarPubMed
134.Wang, KC, et al. Oligodendrocyte-myelin glycoprotein is a Nogo receptor ligand that inhibits neurite outgrowth. Nature 2002; 417:941–944.CrossRefGoogle ScholarPubMed
135.Wang, KC, et al. P75 interacts with the Nogo receptor as a co-receptor for Nogo, MAG and OMgp. Nature 2002; 420:74–78.CrossRefGoogle ScholarPubMed
136.Josephson, A, et al. NOGO mRNA expression in adult and fetal human and rat nervous tissue and in weight drop injury. Exp Neurol 2001; 169:319–328.CrossRefGoogle ScholarPubMed
137.Neumann, S, Woolf, CJ. Regeneration of dorsal column fibers into and beyond the lesion site following adult spinal cord injury. Neuron 1999; 23:83–91.Google ScholarPubMed
138.Neumann, S, et al. Regeneration of sensory axons within the injured spinal cord induced by intraganglionic cAMP elevation. Neuron 2002; 34:885–893.CrossRefGoogle ScholarPubMed
139.Pot, C, et al. Nogo-A expressed in Schwann cells impairs axonal regeneration after peripheral nerve injury. J Cell Biol 2002; 159:29–35.CrossRefGoogle ScholarPubMed
140.Simonen, M, et al. Systemic deletion of the myelin-associated outgrowth inhibitor Nogo-A improves regenerative and plastic responses after spinal cord injury. Neuron 2003; 38:201–211.CrossRefGoogle ScholarPubMed
141.Zheng, B, et al. Lack of enhanced spinal regeneration in Nogo-deficient mice. Neuron 2003; 38:213–224.CrossRefGoogle ScholarPubMed
142.Kim, JE, et al. Axon regeneration in young adult mice lacking Nogo-A/B. Neuron 2003; 38:187–199.CrossRefGoogle ScholarPubMed
143.Woolf, CJ. No Nogo: now where to go? Neuron 2003; 38:153–156.CrossRefGoogle ScholarPubMed
144.Josephson, A, et al. Nogo-receptor gene activity: cellular localization and developmental regulation of mRNA in mice and humans. J Comp Neurol 2002; 453:292–304.CrossRefGoogle ScholarPubMed
145.Hunt, D, et al. Nogo receptor mRNA expression in intact and re-generating CNS neurons. Mol Cell Neurosci 2002; 20:537–552.CrossRefGoogle Scholar
146.Bartsch, U, Kirchhoff, F, Schachner, M. Immunohistological localization of the adhesion molecules L1, N-CAM, and MAG in the developing and adult optic nerve of mice. J Comp Neurol 1989; 284:451–462.CrossRefGoogle ScholarPubMed
147.Favilla, JT, et al. Myelin-associated glycoprotein (MAG) distribution in human central nervous tissue studied immunocytochemically with monoclonal antibody. J Neuroimmunol 1984; 6:19–30.CrossRefGoogle ScholarPubMed
148.deBellard, ME, et al. Myelin-associated glycoprotein inhibits axonal regeneration from a variety of neurons via interaction with a sialoglycoprotein. Mol Cell Neurosci 1996; 7:89–101.CrossRefGoogle ScholarPubMed
149.McKerracher, L, et al. Identification of myelin-associated glycoprotein as a major myelin-derived inhibitor of neurite growth. Neuron 1994; 13:805–811.CrossRefGoogle Scholar
150.Shibata, A, et al. Unique responses of differentiating neuronal growth cones to inhibitory cues presented by oligodendrocytes. J Cell Biol 1998; 142:191–202.CrossRefGoogle ScholarPubMed
151.Song, H, et al. Conversion of neuronal growth cone responses from repulsion to attraction by cyclic nucleotides. Science 1998; 281:1515–1518.CrossRefGoogle ScholarPubMed
152.Cai, D, et al. Neuronal cyclic AMP controls the developmental loss in ability of axons to regenerate. J Neurosci 2001; 21:4731–4739.CrossRefGoogle ScholarPubMed
153.Domeniconi, M, et al. Myelin-associated glycoprotein interacts with the Nogo66 receptor to inhibit neurite outgrowth. Neuron 2002; 35:283–290.CrossRefGoogle ScholarPubMed
154.Yamashita, T, Higuchi, H, Tohyama, M. The p75 receptor transduces the signal from myelin-associated glycoprotein to Rho. J Cell Biol 2002; 157:565–570.CrossRefGoogle ScholarPubMed
155.Niederost, B, et al. Nogo-A and myelin-associated glycoprotein mediate neurite growth inhibition by antagonistic regulation of RhoAand Rac1. J Neurosci 2002; 22:10368–10376.CrossRefGoogle Scholar
156.Wong, ST, et al. Ap75(NTR) and Nogo receptor complex mediates repulsive signaling by myelin-associated glycoprotein. Nat Neurosci 2002; 5:1302–1308.CrossRefGoogle Scholar
157.Kaplan, DR, Miller, FD. Axon growth inhibition: signals from the p75 neurotrophin receptor. Nat Neurosci 2003; 6:435–436.CrossRefGoogle ScholarPubMed
158.Mikol, DD, Gulcher, JR, Stefansson, K. The oligodendrocyte-myelin glycoprotein belongs to a distinct family of proteins and contains the HNK-1 carbohydrate. J Cell Biol 1990; 110:471–479.CrossRefGoogle ScholarPubMed
159.Quarles, RH. Glycoproteins of myelin sheaths. J Mol Neurosci 1997; 8:1–12.CrossRefGoogle ScholarPubMed
160.Spencer, T, et al. New roles for old proteins in adult CNS axonal regeneration. Curr Opin Neurobiol 2003; 13:133–139.CrossRefGoogle ScholarPubMed
161.Eccles, JC, Sherrington, CS. Numbers and contraction values of individual motor units examined in some muscles of the limb. Proc R Soc B 1930; 106:326–357.Google Scholar
162.Sunderland, S. Nerve Injury and Repair. Edinburgh: Churchill Livingstone, 1991.Google Scholar
163.Lundborg, G. Nerve Injury and Repair. Edinburgh: Churchill Livingstone, 1988.Google Scholar
164.Cajal Ramon, Y. Degeneration and Regeneration of the NervousSystem. New York: Hafner publishing Co, 1959.Google Scholar
165.You, S, et al. The expression of the low affinity nerve growth factor receptor in long-term denervated Schwann cells. Glia 1997; 20:87–100.Google Scholar
166.Hall, SM. The biology of chronically denervated Schwann cells. Ann N Y Acad Sci 1999; 883:215–233.CrossRefGoogle ScholarPubMed
167.Ng, CE, Tang, BL. Nogos and the Nogo-66 receptor: factors inhibiting CNS neuron regeneration. J Neurosci Res 2002; 67:559–565.CrossRefGoogle ScholarPubMed
168.Plunet, W, Kwon, BK, Tetzlaff, W. Promoting axonal regeneration in the central nervous system by enhancing the cell body response to axotomy. J Neurosci Res 2002; 68:1–6.CrossRefGoogle ScholarPubMed
169.Boyd, JG, Gordon, T. The neurotrophin receptors, trkB and p75, differentially regulate motor axonal regeneration. J Neurobiol 2001; 49:314–325.CrossRefGoogle ScholarPubMed
170.Fu, SY, Gordon, T. Contributing factors to poor functional recovery after delayed nerve repair: prolonged axotomy. J Neurosci 1995; 15:3876–3885.CrossRefGoogle ScholarPubMed
171.Boyd, JG, Gordon, T. A dose-dependent facilitation and inhibition of peripheral nerve regeneration by brain-derived neurotrophic factor. Eur J Neurosci 2002; 15:613–626.CrossRefGoogle ScholarPubMed
172.Cisterni, C, et al. Efficient gene transfer and expression of biologically active glial cell line-derived neurotrophic factor in rat motoneurons transduced with lentiviral vectors. J Neurochem 2000; 74:1820–1828.CrossRefGoogle ScholarPubMed
173.Hottinger, AF, et al. Complete and long-term rescue of lesioned adult motoneurons by lentiviral-mediated expression of glial cell line-derived neurotrophic factor in the facial nucleus. J Neurosci 2000; 20:5587–5593.CrossRefGoogle ScholarPubMed
174.Lee, M, et al. FK506 promotes functional recovery in crushed rat sciatic nerve. Muscle Nerve 2000; 23:633–640.3.0.CO;2-Q>CrossRefGoogle ScholarPubMed
175.Sulaiman, OA, et al. FK506 increases peripheral nerve regeneration after chronic axotomy but not after chronic Schwann cell denervation. Exp Neurol 2002; 175:127–137.CrossRefGoogle Scholar
176.Sunderland, S. Nerve and Nerve Injuries. Surgery & Hand Surgery. Edinburgh: Churchill Livingstone, 1978;117–188.Google Scholar
177.Sulaiman, OA, Gordon, T. Transforming growth factor-beta and forskolin attenuate the adverse effects of long-term Schwann cell denervation on peripheral nerve regeneration in vivo. Glia 2002; 37:206–218.CrossRefGoogle ScholarPubMed
178.Li, H, Terenghi, G, Hall, SM. Effects of delayed re-innervation on the expression of c-erbB receptors by chronically denervated rat Schwann cells in vivo. Glia 1997; 20:333–347.3.0.CO;2-6>CrossRefGoogle ScholarPubMed
179.Dedkov, EI, et al. Survival of Schwann cells in chronically denervated skeletal muscles. Acta Neuropathol (Berl) 2002; 103:565–574.CrossRefGoogle ScholarPubMed
180.Fu, SY, Gordon, T. The cellular and molecular basis of peripheral nerve regeneration. Mol Neurobiol 1997; 14:67–116.CrossRefGoogle ScholarPubMed
181.Al-Majed, AA, et al. Brief electrical stimulation promotes the speed and accuracy of motor axonal regeneration. J Neurosci 2000; 20:2602–2608.CrossRefGoogle ScholarPubMed
182.Brushart, TM, et al. Electrical stimulation promotes motoneuron regeneration without increasing its speed or conditioning the neuron. J Neurosci 2002; 22:6631–6638.CrossRefGoogle ScholarPubMed
183.Al Majed, AA, Brushart, TM, Gordon, T. Electrical stimulation accelerates and increases expression of BDNF and trkB mRNA in regenerating rat femoral motoneurons. Eur J Neurosci 2000; 12:4381–4390.CrossRefGoogle ScholarPubMed
184.Zafra, F, et al. Activity dependent regulation of BDNF and NGF mRNAs in the rat hippocampus is mediated by non-NMDA glutamate receptors. EMBO J 1990; 9:3545–3550.CrossRefGoogle ScholarPubMed
185.Lu, B, Figurov, A. Role of neurotrophins in synapse development and plasticity. Rev Neurosci 1997; 8:1–12.CrossRefGoogle ScholarPubMed
186.Bender, RA, et al. Enhanced CREB phosphorylation in immature dentate gyrus granule cells precedes neurotrophin expression and indicates a specific role of CREB in granule cell differentiation. Eur J Neurosci 2001; 13:679–686.CrossRefGoogle ScholarPubMed
187.Tong, L, et al. Effects of exercise on gene-expression profile in the rat hippocampus. Neurobiol Dis 2001; 8:1046–1056.CrossRefGoogle ScholarPubMed
188.Al-Majed, AA, Tam, SL, Gordon, T. Concurrent induction of tubulin and GAP-43 mRNA and downregulation of neurofilament mRNA in axotomized femoral motoneurons in response to conditioning electrical stimulation. Mol Cell Neurobiol 2004; (in press).Google Scholar
189.Blesch, A, Lu, P, Tuszynski, MH. Neurotrophic factors, gene therapy, and neural stem cells for spinal cord repair. Brain Res Bull 2002; 57:833–838.CrossRefGoogle ScholarPubMed
190.Uittenbogaard, M, Martinka, DL, Chiaramello, A. The basic helix-loop-helix differentiation factor Nex1/MATH-2 functions as a key activator of the GAP-43 gene. J Neurochem 2003; 84:678–688.CrossRefGoogle ScholarPubMed
191.Bracken, MB, et al. Administration of methylprednisolone for 24 or 48 hours or tirilazad mesylate for 48 hours in the treatment of acute spinal cord injury. Results of the Third National Acute Spinal Cord Injury Randomized Controlled Trial. National Acute Spinal Cord Injury Study. JAMA 1997; 277:1597–1604.CrossRefGoogle ScholarPubMed
192.Bracken, MB, Holford, TR. Neurological and functional status 1 year after acute spinal cord injury: estimates of functional recovery in National Acute Spinal Cord Injury Study II from results modeled in National Acute Spinal Cord Injury Study III. J Neurosurg 2002; 96:259–266.Google ScholarPubMed
193.Hurlbert, RJ, Moulton, R. Why do you prescribe methylprednisolone for acute spinal cord injury? A Canadian perspective and a position statement. Can J Neurol Sci 2002; 29:236–239.CrossRefGoogle Scholar
194.Hauben, E, Schwartz, M. Therapeutic vaccination for spinal cord injury: helping the body to cure itself. Trends Pharmacol Sci 2003; 24:7–12.CrossRefGoogle Scholar
195.Popovich, PG, Jones, TB. Manipulating neuroinflammatory reactions in the injured spinal cord: back to basics. Trends Pharmacol Sci 2003; 24:13–17.CrossRefGoogle ScholarPubMed
196.Giulian, D, et al. Reactive mononuclear phagocytes release neurotoxins after ischemic and traumatic injury to the central nervous system. J Neurosci Res 1993; 36:681–693.CrossRefGoogle ScholarPubMed
197.Blight, AR. Effects of silica on the outcome from experimental spinal cord injury: implication of macrophages in secondary tissue damage. Neuroscience 1994; 60:263–273.CrossRefGoogle ScholarPubMed
198.Giulian, D, Robertson, C. Inhibition of mononuclear phagocytes reduces ischemic injury in the spinal cord. Ann Neurol 1990; 27:33–42.CrossRefGoogle ScholarPubMed
199.Mabon, PJ, Weaver, LC, Dekaban, GA. Inhibition of monocyte/macrophage migration to a spinal cord injury site by an antibody to the integrin alphaD: a potential new anti-inflammatory treatment. Exp Neurol 2000; 166:52–64.CrossRefGoogle Scholar
200. Popovich, PG, et al. Depletion of hematogenous macrophages promotes partial hindlimb recovery and neuroanatomical repair after experimental spinal cord injury. Exp Neurol 1999; 158:351–365.CrossRefGoogle ScholarPubMed
201.Guth, L, et al. Spinal cord injury in the rat: treatment with bacterial lipopolysaccharide and indomethacin enhances cellular repair and locomotor function. Exp Neurol 1994; 126:76–87.CrossRefGoogle ScholarPubMed
202.Ousman, SS, David, S. Lysophosphatidylcholine induces rapid recruitment and activation of macrophages in the adult mouse spinal cord. Glia 2000; 30:92–104.3.0.CO;2-W>CrossRefGoogle ScholarPubMed
203.Ousman, SS, David, S. MIP-1alpha, MCP-1, GM-CSF, and TNF- alpha control the immune cell response that mediates rapid phagocytosis of myelin from the adult mouse spinal cord. J Neurosci 2001; 21:4649–4656.CrossRefGoogle ScholarPubMed
204.Fiedler, M, et al. An engineered IN-1 F(ab) fragment with improved affinity for the Nogo-A axonal growth inhibitor permits immunochemical detection and shows enhanced neutralizing activity. Protein Eng 2002; 15:931–941.CrossRefGoogle ScholarPubMed
205.Fournier, AE, et al. Truncated soluble Nogo receptor binds Nogo-66 and blocks inhibition of axon growth by myelin. J Neurosci 2002; 22:8876–8883.CrossRefGoogle ScholarPubMed
206.GrandPre, T, Li, S, Strittmatter, SM. Nogo-66 receptor antagonist peptide promotes axonal regeneration. Nature 2002; 417:547–551.CrossRefGoogle ScholarPubMed
207.Song, HJ, Ming, GL, Poo, MM. cAMP-induced switching in turning direction of nerve growth cones. Nature 1997; 388:275–279.CrossRefGoogle ScholarPubMed
208.Qiu, J, et al. Spinal axon regeneration induced by elevation of cyclic AMP. Neuron 2002; 34:895–903.CrossRefGoogle ScholarPubMed
209.Cai, D, Deng, K, Mellado, W, et al. Arginase I and polyamines act downstream from cyclic AMP in overcoming inhibition of axonal growth MAG and myelin in vitro. Neuron. 2002 Aug 15;35(4):711–719.Google ScholarPubMed
210.Cui, Q, et al. Intraocular elevation of cyclic AMP potentiates ciliary neurotrophic factor-induced regeneration of adult rat retinal ganglion cell axons. Mol Cell Neurosci 2003; 22:49–61.CrossRefGoogle ScholarPubMed
211.Li, Y, Decherchi, P, Raisman, G. Transplantation of olfactory ensheathing cells into spinal cord lesions restores breathing and climbing. J Neurosci 2003; 23:727–731.CrossRefGoogle ScholarPubMed
212.Ramon-Cueto, A, et al. Long-distance axonal regeneration in the transected adult rat spinal cord is promoted by olfactory ensheathing glia transplants. J Neurosci 1998; 18:3803–3815.CrossRefGoogle ScholarPubMed
213.Bradbury, EJ, et al. Chondroitinase ABC promotes functional recovery after spinal cord injury. Nature 2002; 416:636–640.CrossRefGoogle ScholarPubMed
214.Schnell, L, et al. Neurotrophin-3 enhances sprouting of corticospinal tract during development and after adult spinal cord lesion. Nature 1994; 367:170–173.CrossRefGoogle ScholarPubMed