Hostname: page-component-586b7cd67f-t7fkt Total loading time: 0 Render date: 2024-11-25T15:47:54.704Z Has data issue: false hasContentIssue false

Extrinsic and intrinsic factors controlling axonal regeneration after spinal cord injury

Published online by Cambridge University Press:  08 December 2009

Fardad T. Afshari*
Affiliation:
Centre for Brain Repair, University of Cambridge, Cambridge, UK.
Sunil Kappagantula
Affiliation:
Centre for Brain Repair, University of Cambridge, Cambridge, UK.
James W. Fawcett
Affiliation:
Centre for Brain Repair, University of Cambridge, Cambridge, UK.
*
*Corresponding author: Fardad T. Afshari, Centre for Brain Repair, University of Cambridge, Forvie Site, Robinson Way, Cambridge, CB2 0PY, UK. Tel: +44 1223 334121; Fax: +44 1223 331174; E-mail: [email protected]

Abstract

Spinal cord injury is one of the most devastating conditions that affects the central nervous system. It can lead to permanent disability and there are around two million people affected worldwide. After injury, accumulation of myelin debris and formation of an inhibitory glial scar at the site of injury leads to a physical and chemical barrier that blocks axonal growth and regeneration. The mammalian central nervous system thus has a limited intrinsic ability to repair itself after injury. To improve axonal outgrowth and promote functional recovery, it is essential to identify the various intrinsic and extrinsic factors controlling regeneration and navigation of axons within the inhibitory environment of the central nervous system. Recent advances in spinal cord research have opened new avenues for the exploration of potential targets for repairing the cord and improving functional recovery after trauma. Here, we discuss some of the important key molecules that could be harnessed for repairing spinal cord injury.

Type
Review Article
Copyright
Copyright © Cambridge University Press 2009

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

References

1Oudega, M. (2007) Schwann cell and olfactory ensheathing cell implantation for repair of the contused spinal cord. Acta Physiologica 189, 181-189CrossRefGoogle ScholarPubMed
2Kwon, B.K., Borisoff, J.F. and Tetzlaff, W. (2002) Molecular targets for therapeutic intervention after spinal cord injury. Molecular Interventions 2, 244-258CrossRefGoogle ScholarPubMed
3Silver, J. and Miller, J.H. (2004) Regeneration beyond the glial scar. Nature Reviews Neuroscience 5, 146-156CrossRefGoogle ScholarPubMed
4Fawcett, J.W. and Asher, R.A. (1999) The glial scar and central nervous system repair. Brain Research Bulletin 49, 377-391CrossRefGoogle ScholarPubMed
5Okada, S. et al. (2004) Blockade of interleukin-6 receptor suppresses reactive astrogliosis and ameliorates functional recovery in experimental spinal cord injury. Journal of Neuroscience Research 76, 265-276CrossRefGoogle ScholarPubMed
6Nakamura, M. et al. (2005) Role of IL-6 in spinal cord injury in a mouse model. Clinical Reviews in Allergy and Immunology 28, 197-204CrossRefGoogle ScholarPubMed
7Faulkner, J.R. et al. (2004) Reactive astrocytes protect tissue and preserve function after spinal cord injury. Journal of Neuroscience 24, 2143-2155CrossRefGoogle ScholarPubMed
8Bundesen, L.Q. et al. (2003) Ephrin-B2 and EphB2 regulation of astrocyte-meningeal fibroblast interactions in response to spinal cord lesions in adult rats. Journal of Neuroscience 23, 7789-7800CrossRefGoogle ScholarPubMed
9Abnet, K., Fawcett, J.W. and Dunnett, S.B. (1991) Interactions between meningeal cells and astrocytes in vivo and in vitro. Brain Research Developmental Brain Research 59, 187-196CrossRefGoogle ScholarPubMed
10Windle, W.F., Clemente, C.D. and Chambers, W.W. (1952) Inhibition of formation of a glial barrier as a means of permitting a peripheral nerve to grow into the brain. Journal of Comparative Neurology 96, 359-369CrossRefGoogle ScholarPubMed
11Kwok, J.C. et al. (2008) Proteoglycans in the central nervous system: Plasticity, regeneration and their stimulation with chondroitinase ABC. Restorative Neurology and Neuroscience 26, 131-145Google ScholarPubMed
12Niclou, S.P., Ehlert, E.M. and Verhaagen, J. (2006) Chemorepellent axon guidance molecules in spinal cord injury. Journal of Neurotrauma 23, 409-421CrossRefGoogle ScholarPubMed
13Asher, R.A. et al. (2000) Neurocan is upregulated in injured brain and in cytokine-treated astrocytes. Journal of Neuroscience 20, 2427-2438CrossRefGoogle ScholarPubMed
14Yong, V.W. et al. (1991) Gamma-interferon promotes proliferation of adult human astrocytes in vitro and reactive gliosis in the adult mouse brain in vivo. Proceedings of the National Academy of Sciences of the United States of America 88, 7016-7020CrossRefGoogle ScholarPubMed
15Giulian, D. et al. (1988) Interleukin-1 injected into mammalian brain stimulates astrogliosis and neovascularization. Journal of Neuroscience 8, 2485-2490CrossRefGoogle ScholarPubMed
16Grados-Munro, E.M. and Fournier, A.E. (2003) Myelin-associated inhibitors of axon regeneration. Journal of Neuroscience Research 74, 479-485CrossRefGoogle ScholarPubMed
17McGee, A.W. and Strittmatter, S.M. (2003) The Nogo-66 receptor: focusing myelin inhibition of axon regeneration. Trends in Neurosciences 26, 193-198CrossRefGoogle ScholarPubMed
18Caroni, P. and Schwab, M.E. (1988) Two membrane protein fractions from rat central myelin with inhibitory properties for neurite growth and fibroblast spreading. Journal of Cell Biology 106, 1281-1288CrossRefGoogle ScholarPubMed
19Caroni, P. and Schwab, M.E. (1988) Antibody against myelin-associated inhibitor of neurite growth neutralizes nonpermissive substrate properties of CNS white matter. Neuron 1, 85-96CrossRefGoogle ScholarPubMed
20Schnell, L. and Schwab, M.E. (1990) Axonal regeneration in the rat spinal cord produced by an antibody against myelin-associated neurite growth inhibitors. Nature 343, 269-272CrossRefGoogle ScholarPubMed
21Fouad, K., Klusman, I. and Schwab, M.E. (2004) Regenerating corticospinal fibers in the Marmoset (Callitrix jacchus) after spinal cord lesion and treatment with the anti-Nogo-A antibody IN-1. European Journal of Neuroscience 20, 2479-2482CrossRefGoogle ScholarPubMed
22Freund, P. et al. (2006) Nogo-A-specific antibody treatment enhances sprouting and functional recovery after cervical lesion in adult primates. Nature Medicine 12, 790-792CrossRefGoogle ScholarPubMed
23Blight, A.R. and Tuszynski, M.H. (2006) Clinical trials in spinal cord injury. Journal of Neurotrauma 23, 586-593CrossRefGoogle ScholarPubMed
24Chen, M.S. et al. (2000) Nogo-A is a myelin-associated neurite outgrowth inhibitor and an antigen for monoclonal antibody IN-1. Nature 403, 434-439CrossRefGoogle Scholar
25Hu, F. and Strittmatter, S.M. (2008) The N-terminal domain of Nogo-A inhibits cell adhesion and axonal outgrowth by an integrin-specific mechanism. Journal of Neuroscience 28, 1262-1269CrossRefGoogle ScholarPubMed
26Fournier, A.E., GrandPre, T. and Strittmatter, S.M. (2001) Identification of a receptor mediating Nogo-66 inhibition of axonal regeneration. Nature 409, 341-346CrossRefGoogle ScholarPubMed
27Wang, K.C. et al. (2002) P75 interacts with the Nogo receptor as a co-receptor for Nogo, MAG and OMgp. Nature 420, 74-78CrossRefGoogle ScholarPubMed
28Mosyak, L. et al. (2006) The structure of the Lingo-1 ectodomain, a module implicated in central nervous system repair inhibition. Journal of Biological Chemistry 281, 36378-36390CrossRefGoogle ScholarPubMed
29GrandPre, T., Li, S. and Strittmatter, S.M. (2002) Nogo-66 receptor antagonist peptide promotes axonal regeneration. Nature 417, 547-551CrossRefGoogle ScholarPubMed
30Zheng, B. et al. (2003) Lack of enhanced spinal regeneration in Nogo-deficient mice. Neuron 38, 213-224CrossRefGoogle ScholarPubMed
31Simonen, M. et al. (2003) Systemic deletion of the myelin-associated outgrowth inhibitor Nogo-A improves regenerative and plastic responses after spinal cord injury. Neuron 38, 201-211CrossRefGoogle ScholarPubMed
32Kim, J.E. et al. (2003) Axon regeneration in young adult mice lacking Nogo-A/B. Neuron 38, 187-199CrossRefGoogle ScholarPubMed
33Lee, J.K. et al. (2009) Reassessment of corticospinal tract regeneration in Nogo-deficient mice. Journal of Neuroscience 29, 8649-8654CrossRefGoogle ScholarPubMed
34Martini, R. (1994) Expression and functional roles of neural cell surface molecules and extracellular matrix components during development and regeneration of peripheral nerves. Journal of Neurocytology 23, 1-28CrossRefGoogle ScholarPubMed
35Mukhopadhyay, G. et al. (1994) A novel role for myelin-associated glycoprotein as an inhibitor of axonal regeneration. Neuron 13, 757-767CrossRefGoogle ScholarPubMed
36McKerracher, L. et al. (1994) Identification of myelin-associated glycoprotein as a major myelin-derived inhibitor of neurite growth. Neuron 13, 805-811CrossRefGoogle Scholar
37Schnaar, R.L. and Lopez, P.H. (2009) Myelin-associated glycoprotein and its axonal receptors. Journal of Neuroscience Research 87, 3267-3276CrossRefGoogle ScholarPubMed
38Mehta, N.R. et al. (2007) Gangliosides and Nogo receptors independently mediate myelin-associated glycoprotein inhibition of neurite outgrowth in different nerve cells. Journal of Biological Chemistry 282, 27875-27886CrossRefGoogle ScholarPubMed
39Domeniconi, M. et al. (2002) Myelin-associated glycoprotein interacts with the Nogo66 receptor to inhibit neurite outgrowth. Neuron 35, 283-290CrossRefGoogle ScholarPubMed
40Mikol, D.D. and Stefansson, K. (1988) A phosphatidylinositol-linked peanut agglutinin-binding glycoprotein in central nervous system myelin and on oligodendrocytes. Journal of Cell Biology 106, 1273-1279CrossRefGoogle ScholarPubMed
41Kottis, V. et al. (2002) Oligodendrocyte-myelin glycoprotein (OMgp) is an inhibitor of neurite outgrowth. Journal of Neurochemistry 82, 1566-1569CrossRefGoogle ScholarPubMed
42Wang, K.C. et al. (2002) Oligodendrocyte-myelin glycoprotein is a Nogo receptor ligand that inhibits neurite outgrowth. Nature 417, 941-944CrossRefGoogle ScholarPubMed
43Niederost, B. et al. (2002) Nogo-A and myelin-associated glycoprotein mediate neurite growth inhibition by antagonistic regulation of RhoA and Rac1. Journal of Neuroscience 22, 10368-10376CrossRefGoogle ScholarPubMed
44Yamashita, T. et al. (2005) Multiple signals regulate axon regeneration through the Nogo receptor complex. Molecular Neurobiology 32, 105-111CrossRefGoogle ScholarPubMed
45Gallo, V., Bertolotto, A. and Levi, G. (1987) The proteoglycan chondroitin sulfate is present in a subpopulation of cultured astrocytes and in their precursors. Developmental Biology 123, 282-285CrossRefGoogle Scholar
46Johnson-Green, P.C., Dow, K.E. and Riopelle, R.J. (1991) Characterization of glycosaminoglycans produced by primary astrocytes in vitro. Glia 4, 314-321CrossRefGoogle ScholarPubMed
47Crespo, D. et al. (2007) How does chondroitinase promote functional recovery in the damaged CNS? Experimental Neurology 206, 159-171CrossRefGoogle ScholarPubMed
48Dou, C.L. and Levine, J.M. (1994) Inhibition of neurite growth by the NG2 chondroitin sulfate proteoglycan. Journal of Neuroscience 14, 7616-7628CrossRefGoogle ScholarPubMed
49McKeon, R.J., Hoke, A. and Silver, J. (1995) Injury-induced proteoglycans inhibit the potential for laminin-mediated axon growth on astrocytic scars. Experimental Neurology 136, 32-43CrossRefGoogle ScholarPubMed
50Moon, L.D. et al. (2001) Regeneration of CNS axons back to their target following treatment of adult rat brain with chondroitinase ABC. Nature Neuroscience 4, 465-466CrossRefGoogle ScholarPubMed
51Caggiano, A.O. et al. (2005) Chondroitinase ABCI improves locomotion and bladder function following contusion injury of the rat spinal cord. Journal of Neurotrauma 22, 226-239CrossRefGoogle ScholarPubMed
52Bradbury, E.J. et al. (2002) Chondroitinase ABC promotes functional recovery after spinal cord injury. Nature 416, 636-640CrossRefGoogle ScholarPubMed
53Cafferty, W.B. et al. (2007) Functional axonal regeneration through astrocytic scar genetically modified to digest chondroitin sulfate proteoglycans. Journal of Neuroscience 27, 2176-2185CrossRefGoogle ScholarPubMed
54Yada, T. et al. (2003) Chondroitin sulfate synthase-2. Molecular cloning and characterization of a novel human glycosyltransferase homologous to chondroitin sulfate glucuronyltransferase, which has dual enzymatic activities. Journal of Biological Chemistry 278, 30235-30247CrossRefGoogle ScholarPubMed
55Kitagawa, H. et al. (1997) Regulation of chondroitin sulfate biosynthesis by specific sulfation: acceptor specificity of serum beta-GalNAc transferase revealed by structurally defined oligosaccharides. Glycobiology 7, 531-537CrossRefGoogle ScholarPubMed
56Laabs, T.L. et al. (2007) Inhibiting glycosaminoglycan chain polymerization decreases the inhibitory activity of astrocyte-derived chondroitin sulfate proteoglycans. Journal of Neuroscience 27, 14494-14501CrossRefGoogle ScholarPubMed
57Zhou, F.Q. et al. (2006) Neurotrophins support regenerative axon assembly over CSPGs by an ECM-integrin-independent mechanism. Journal of Cell Science 119, 2787-2796CrossRefGoogle ScholarPubMed
58Smith-Thomas, L.C. et al. (1994) An inhibitor of neurite outgrowth produced by astrocytes. Journal of Cell Science 107, 1687-1695CrossRefGoogle ScholarPubMed
59Yamaguchi, Y., Mann, D.M. and Ruoslahti, E. (1990) Negative regulation of transforming growth factor-beta by the proteoglycan decorin. Nature 346, 281-284CrossRefGoogle ScholarPubMed
60Davies, J.E. et al. (2004) Decorin suppresses neurocan, brevican, phosphacan and NG2 expression and promotes axon growth across adult rat spinal cord injuries. European Journal of Neuroscience 19, 1226-1242CrossRefGoogle ScholarPubMed
61Santra, M., Reed, C.C. and Iozzo, R.V. (2002) Decorin binds to a narrow region of the epidermal growth factor (EGF) receptor, partially overlapping but distinct from the EGF-binding epitope. Journal of Biological Chemistry 277, 35671-35681CrossRefGoogle ScholarPubMed
62Minor, K. et al. (2008) Decorin promotes robust axon growth on inhibitory CSPGs and myelin via a direct effect on neurons. Neurobiology of Disease 32, 88-95CrossRefGoogle Scholar
63Zou, Y. et al. (2000) Squeezing axons out of the gray matter: a role for slit and semaphorin proteins from midline and ventral spinal cord. Cell 102, 363-375CrossRefGoogle ScholarPubMed
64Raper, J.A. (2000) Semaphorins and their receptors in vertebrates and invertebrates. Current Opinion in Neurobiology 10, 88-94CrossRefGoogle ScholarPubMed
65Pasterkamp, R.J., Anderson, P.N. and Verhaagen, J. (2001) Peripheral nerve injury fails to induce growth of lesioned ascending dorsal column axons into spinal cord scar tissue expressing the axon repellent Semaphorin3A. European Journal of Neuroscience 13, 457-471CrossRefGoogle ScholarPubMed
66Pasterkamp, R.J., Giger, R.J. and Verhaagen, J. (1998) Regulation of semaphorin III/collapsin-1 gene expression during peripheral nerve regeneration. Experimental Neurology 153, 313-327CrossRefGoogle ScholarPubMed
67Kikuchi, K. et al. (2003) In vitro and in vivo characterization of a novel semaphorin 3A inhibitor, SM-216289 or xanthofulvin. Journal of Biological Chemistry 278, 42985-42991CrossRefGoogle ScholarPubMed
68Kaneko, S. et al. (2006) A selective Sema3A inhibitor enhances regenerative responses and functional recovery of the injured spinal cord. Nature Medicine 12, 1380-1389CrossRefGoogle ScholarPubMed
69Klein, R. (2004) Eph/ephrin signaling in morphogenesis, neural development and plasticity. Current Opinion in Cell Biology 16, 580-589CrossRefGoogle ScholarPubMed
70Goldshmit, Y., McLenachan, S. and Turnley, A. (2006) Roles of Eph receptors and ephrins in the normal and damaged adult CNS. Brain Research Reviews 52, 327-345CrossRefGoogle ScholarPubMed
71Gale, N.W. et al. (1996) Eph receptors and ligands comprise two major specificity subclasses and are reciprocally compartmentalized during embryogenesis. Neuron 17, 9-19CrossRefGoogle ScholarPubMed
72Torres, R. et al. (1998) PDZ proteins bind, cluster, and synaptically colocalize with Eph receptors and their ephrin ligands. Neuron 21, 1453-1463CrossRefGoogle ScholarPubMed
73Kullander, K. and Klein, R. (2002) Mechanisms and functions of Eph and ephrin signalling. Nature Reviews Molecular Cell Biology 3, 475-486CrossRefGoogle ScholarPubMed
74Gao, P.P. et al. (1998) Regulation of thalamic neurite outgrowth by the Eph ligand ephrin-A5: implications in the development of thalamocortical projections. Proceedings of the National Academy of Sciences of the United States of America 95, 5329-5334CrossRefGoogle ScholarPubMed
75Kullander, K. et al. (2001) Ephrin-B3 is the midline barrier that prevents corticospinal tract axons from recrossing, allowing for unilateral motor control. Genes and Development 15, 877-888CrossRefGoogle ScholarPubMed
76Benson, M.D. et al. (2005) Ephrin-B3 is a myelin-based inhibitor of neurite outgrowth. Proceedings of the National Academy of Sciences of the United States of America 102, 10694-10699CrossRefGoogle ScholarPubMed
77Willson, C.A. et al. (2002) Upregulation of EphA receptor expression in the injured adult rat spinal cord. Cell Transplantation 11, 229-239CrossRefGoogle ScholarPubMed
78Miranda, J.D. et al. (1999) Induction of Eph B3 after spinal cord injury. Experimental Neurology 156, 218-222CrossRefGoogle ScholarPubMed
79Fabes, J. et al. (2006) Accumulation of the inhibitory receptor EphA4 may prevent regeneration of corticospinal tract axons following lesion. European Journal of Neuroscience 23, 1721-1730CrossRefGoogle ScholarPubMed
80Kliffen, M. et al. (1997) Increased expression of angiogenic growth factors in age-related maculopathy. British Journal of Ophthalmology 81, 154-162CrossRefGoogle ScholarPubMed
81Goldshmit, Y. et al. (2004) Axonal regeneration and lack of astrocytic gliosis in EphA4-deficient mice. Journal of Neuroscience 24, 10064-10073CrossRefGoogle ScholarPubMed
82Fabes, J. et al. (2007) Regeneration-enhancing effects of EphA4 blocking peptide following corticospinal tract injury in adult rat spinal cord. European Journal of Neuroscience 26, 2496-2505CrossRefGoogle ScholarPubMed
83Lawrenson, I.D. et al. (2002) Ephrin-A5 induces rounding, blebbing and de-adhesion of EphA3-expressing 293T and melanoma cells by CrkII and Rho-mediated signalling. Journal of Cell Science 115, 1059-1072CrossRefGoogle ScholarPubMed
84Miao, H. et al. (2000) Activation of EphA2 kinase suppresses integrin function and causes focal-adhesion-kinase dephosphorylation. Nature Cell Biology 2, 62-69CrossRefGoogle ScholarPubMed
85Yamaguchi, Y. et al. (2001) RhoA inhibits the nerve growth factor-induced Rac1 activation through Rho-associated kinase-dependent pathway. Journal of Biological Chemistry 276, 18977-18983CrossRefGoogle ScholarPubMed
86Rutishauser, U. (2008) Polysialic acid in the plasticity of the developing and adult vertebrate nervous system. Nature Reviews Neuroscience 9, 26-35CrossRefGoogle ScholarPubMed
87Finne, J. et al. (1983) Occurrence of alpha 2–8 linked polysialosyl units in a neural cell adhesion molecule. Biochemical and Biophysical Research Communications 112, 482-487CrossRefGoogle Scholar
88Kiss, J.Z. et al. (2001) The role of neural cell adhesion molecules in plasticity and repair. Brain Research Reviews 36, 175-184CrossRefGoogle ScholarPubMed
89Becker, C.G. et al. (1996) The polysialic acid modification of the neural cell adhesion molecule is involved in spatial learning and hippocampal long-term potentiation. Journal of Neuroscience Research 45, 143-1523.0.CO;2-A>CrossRefGoogle ScholarPubMed
90Hoyk, Z., Parducz, A. and Theodosis, D.T. (2001) The highly sialylated isoform of the neural cell adhesion molecule is required for estradiol-induced morphological synaptic plasticity in the adult arcuate nucleus. European Journal of Neuroscience 13, 649-656CrossRefGoogle ScholarPubMed
91Hu, H. et al. (1996) The role of polysialic acid in migration of olfactory bulb interneuron precursors in the subventricular zone. Neuron 16, 735-743CrossRefGoogle ScholarPubMed
92Dusart, I. et al. (1999) Late axonal sprouting of injured Purkinje cells and its temporal correlation with permissive changes in the glial scar. Journal of Comparative Neurology 408, 399-4183.0.CO;2-2>CrossRefGoogle ScholarPubMed
93El Maarouf, A., Petridis, A.K. and Rutishauser, U. (2006) Use of polysialic acid in repair of the central nervous system. Proceedings of the National Academy of Sciences of the United States of America 103, 16989-16994CrossRefGoogle ScholarPubMed
94Zhang, Y. et al. (2007) Induced expression of polysialic acid in the spinal cord promotes regeneration of sensory axons. Molecular and Cellular Neurosciences 35, 109-119CrossRefGoogle ScholarPubMed
95Zhang, Y. et al. (2007) Lentiviral-mediated expression of polysialic acid in spinal cord and conditioning lesion promote regeneration of sensory axons into spinal cord. Molecular Therapy 15, 1796-1804CrossRefGoogle ScholarPubMed
96Marino, P. et al. (2009) A polysialic acid mimetic peptide promotes functional recovery in a mouse model of spinal cord injury. Experimental Neurology 219, 163-174CrossRefGoogle Scholar
97Lu, P. and Tuszynski, M.H. (2008) Growth factors and combinatorial therapies for CNS regeneration. Experimental Neurology 209, 313-320CrossRefGoogle ScholarPubMed
98Ramer, M.S., Priestley, J.V. and McMahon, S.B. (2000) Functional regeneration of sensory axons into the adult spinal cord. Nature 403, 312-316CrossRefGoogle ScholarPubMed
99Kobayashi, N.R. et al. (1997) BDNF and NT-4/5 prevent atrophy of rat rubrospinal neurons after cervical axotomy, stimulate GAP-43 and Talpha1-tubulin mRNA expression, and promote axonal regeneration. Journal of Neuroscience 17, 9583-9595CrossRefGoogle ScholarPubMed
100Schnell, L. et al. (1994) Neurotrophin-3 enhances sprouting of corticospinal tract during development and after adult spinal cord lesion. Nature 367, 170-173CrossRefGoogle ScholarPubMed
101Blesch, A. et al. (2004) Axonal responses to cellularly delivered NT-4/5 after spinal cord injury. Molecular and Cellular Neurosciences 27, 190-201CrossRefGoogle ScholarPubMed
102Blesch, A. and Tuszynski, M.H. (2003) Cellular GDNF delivery promotes growth of motor and dorsal column sensory axons after partial and complete spinal cord transections and induces remyelination. Journal of Comparative Neurology 467, 403-417CrossRefGoogle ScholarPubMed
103Bennett, D.L. et al. (2006) Artemin has potent neurotrophic actions on injured C-fibres. Journal of the Peripheral Nervous System 11, 330-345CrossRefGoogle ScholarPubMed
104Zhou, Z. et al. (2009) HSV-mediated transfer of artemin overcomes myelin inhibition to improve outcome after spinal cord injury. Molecular Therapy 17, 1173-1179CrossRefGoogle ScholarPubMed
105Park, S. and Hong, Y.W. (2006) Transcriptional regulation of artemin is related to neurite outgrowth and actin polymerization in mature DRG neurons. Neuroscience Letters 404, 61-66CrossRefGoogle ScholarPubMed
106Paveliev, M., Airaksinen, M.S. and Saarma, M. (2004) GDNF family ligands activate multiple events during axonal growth in mature sensory neurons. Molecular and Cellular Neurosciences 25, 453-459CrossRefGoogle ScholarPubMed
107Block, M.L., Zecca, L. and Hong, J.S. (2007) Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nature Reviews Neuroscience 8, 57-69CrossRefGoogle ScholarPubMed
108Hashimoto, M. et al. (2005) Inflammation-induced GDNF improves locomotor function after spinal cord injury. Neuroreport 16, 99-102CrossRefGoogle ScholarPubMed
109Dougherty, K.D., Dreyfus, C.F. and Black, I.B. (2000) Brain-derived neurotrophic factor in astrocytes, oligodendrocytes, and microglia/macrophages after spinal cord injury. Neurobiology of Disease 7, 574-585CrossRefGoogle ScholarPubMed
110Shechter, R. et al. (2009) Infiltrating blood-derived macrophages are vital cells playing an anti-inflammatory role in recovery from spinal cord injury in mice. PLoS Medicine 6, e1000113CrossRefGoogle ScholarPubMed
111Rolls, A. et al. (2008) Two faces of chondroitin sulfate proteoglycan in spinal cord repair: a role in microglia/macrophage activation. PLoS Medicine 5, e171CrossRefGoogle ScholarPubMed
112Raivich, G. et al. (2004) The AP-1 transcription factor c-Jun is required for efficient axonal regeneration. Neuron 43, 57-67CrossRefGoogle ScholarPubMed
113Skene, J.H. (1989) Axonal growth-associated proteins. Annual Review of Neuroscience 12, 127-156CrossRefGoogle ScholarPubMed
114Qiu, J. et al. (2005) Conditioning injury-induced spinal axon regeneration requires signal transducer and activator of transcription 3 activation. Journal of Neuroscience 25, 1645-1653CrossRefGoogle ScholarPubMed
115Rossi, F., Buffo, A. and Strata, P. (2001) Regulation of intrinsic regenerative properties and axonal plasticity in cerebellar Purkinje cells. Restor Neurol Neurosci 19, 85-94Google ScholarPubMed
116Ziv, N.E. and Spira, M.E. (1997) Localized and transient elevations of intracellular Ca2+ induce the dedifferentiation of axonal segments into growth cones. Journal of Neuroscience 17, 3568-3579CrossRefGoogle ScholarPubMed
117Chierzi, S. et al. (2005) The ability of axons to regenerate their growth cones depends on axonal type and age, and is regulated by calcium, cAMP and ERK. European Journal of Neuroscience 21, 2051-2062CrossRefGoogle ScholarPubMed
118Xie, X.Y. and Barrett, J.N. (1991) Membrane resealing in cultured rat septal neurons after neurite transection: evidence for enhancement by Ca(2+)-triggered protease activity and cytoskeletal disassembly. Journal of Neuroscience 11, 3257-3267CrossRefGoogle ScholarPubMed
119Yoo, S. et al. (2003) Plasmalemmal sealing of transected mammalian neurites is a gradual process mediated by Ca(2+)-regulated proteins. Journal of Neuroscience Research 74, 541-551CrossRefGoogle ScholarPubMed
120Spira, M.E. et al. (2003) Critical calpain-dependent ultrastructural alterations underlie the transformation of an axonal segment into a growth cone after axotomy of cultured Aplysia neurons. Journal of Comparative Neurology 457, 293-312CrossRefGoogle ScholarPubMed
121Chu, G.K. and Tator, C.H. (2001) Calcium influx is necessary for optimal regrowth of transected neurites of rat sympathetic ganglion neurons in vitro. Neuroscience 102, 945-957CrossRefGoogle ScholarPubMed
122Gitler, D. and Spira, M.E. (1998) Real time imaging of calcium-induced localized proteolytic activity after axotomy and its relation to growth cone formation. Neuron 20, 1123-1135CrossRefGoogle ScholarPubMed
123Cai, D. et al. (1999) Prior exposure to neurotrophins blocks inhibition of axonal regeneration by MAG and myelin via a cAMP-dependent mechanism. Neuron 22, 89-101CrossRefGoogle Scholar
124Li, Y. et al. (2003) Axon regeneration in goldfish and rat retinal ganglion cells: differential responsiveness to carbohydrates and cAMP. Journal of Neuroscience 23, 7830-7838CrossRefGoogle ScholarPubMed
125Qiu, J. et al. (2002) Spinal axon regeneration induced by elevation of cyclic AMP. Neuron 34, 895-903CrossRefGoogle ScholarPubMed
126Qiu, J., Cai, D. and Filbin, M.T. (2002) A role for cAMP in regeneration during development and after injury. Progress in Brain Research 137, 381-387CrossRefGoogle ScholarPubMed
127Meyer-Franke, A. et al. (1998) Depolarization and cAMP elevation rapidly recruit TrkB to the plasma membrane of CNS neurons. Neuron 21, 681-693CrossRefGoogle Scholar
128Gao, Y. et al. (2003) Neurotrophins elevate cAMP to reach a threshold required to overcome inhibition by MAG through extracellular signal-regulated kinase-dependent inhibition of phosphodiesterase. Journal of Neuroscience 23, 11770-11777CrossRefGoogle Scholar
129Lange, P.S. et al. (2004) Novel roles for arginase in cell survival, regeneration, and translation in the central nervous system. Journal of Nutrition 134, 2812S-2817SCrossRefGoogle ScholarPubMed
130Neumann, S. and Woolf, C.J. (1999) Regeneration of dorsal column fibers into and beyond the lesion site following adult spinal cord injury. Neuron 23, 83-91CrossRefGoogle ScholarPubMed
131Cai, D. et al. (2002) Arginase I and polyamines act downstream from cyclic AMP in overcoming inhibition of axonal growth MAG and myelin in vitro. Neuron 35, 711-719CrossRefGoogle ScholarPubMed
132Cao, Z. et al. (2006) The cytokine interleukin-6 is sufficient but not necessary to mimic the peripheral conditioning lesion effect on axonal growth. Journal of Neuroscience 26, 5565-5573CrossRefGoogle Scholar
133Domowicz, M.S. et al. (2008) Aggrecan is expressed by embryonic brain glia and regulates astrocyte development. Developmental Biology 315, 114-124CrossRefGoogle ScholarPubMed
134Schreyer, D.J. and Skene, J.H. (1993) Injury-associated induction of GAP-43 expression displays axon branch specificity in rat dorsal root ganglion neurons. Journal of Neurobiology 24, 959-970CrossRefGoogle ScholarPubMed
135Seijffers, R., Allchorne, A.J. and Woolf, C.J. (2006) The transcription factor ATF-3 promotes neurite outgrowth. Molecular and Cellular Neurosciences 32, 143-154CrossRefGoogle ScholarPubMed
136Atwal, J.K. et al. (2000) The TrkB-Shc site signals neuronal survival and local axon growth via MEK and P13-kinase. Neuron 27, 265-277CrossRefGoogle ScholarPubMed
137Liu, R.Y. and Snider, W.D. (2001) Different signaling pathways mediate regenerative versus developmental sensory axon growth. Journal of Neuroscience 21, RC164CrossRefGoogle ScholarPubMed
138Markus, A., Zhong, J. and Snider, W.D. (2002) Raf and akt mediate distinct aspects of sensory axon growth. Neuron 35, 65-76CrossRefGoogle ScholarPubMed
139Gallo, G. and Letourneau, P.C. (1998) Localized sources of neurotrophins initiate axon collateral sprouting. Journal of Neuroscience 18, 5403-5414CrossRefGoogle ScholarPubMed
140Gadient, R.A. and Otten, U.H. (1997) Interleukin-6 (IL-6)–a molecule with both beneficial and destructive potentials. Progress in Neurobiology 52, 379-390CrossRefGoogle ScholarPubMed
141Ishizaki, T. et al. (2000) Pharmacological properties of Y-27632, a specific inhibitor of rho-associated kinases. Molecular Pharmacology 57, 976-983Google ScholarPubMed
142Dergham, P. et al. (2002) Rho signaling pathway targeted to promote spinal cord repair. Journal of Neuroscience 22, 6570-6577CrossRefGoogle ScholarPubMed
143Monnier, P.P. et al. (2003) The Rho/ROCK pathway mediates neurite growth-inhibitory activity associated with the chondroitin sulfate proteoglycans of the CNS glial scar. Molecular and Cellular Neurosciences 22, 319-330CrossRefGoogle ScholarPubMed
144Borisoff, J.F. et al. (2003) Suppression of Rho-kinase activity promotes axonal growth on inhibitory CNS substrates. Molecular and Cellular Neurosciences 22, 405-416CrossRefGoogle ScholarPubMed
145Chan, C.C. et al. (2005) Dose-dependent beneficial and detrimental effects of ROCK inhibitor Y27632 on axonal sprouting and functional recovery after rat spinal cord injury. Experimental Neurology 196, 352-364CrossRefGoogle ScholarPubMed
146Fournier, A.E., Takizawa, B.T. and Strittmatter, S.M. (2003) Rho kinase inhibition enhances axonal regeneration in the injured CNS. Journal of Neuroscience 23, 1416-1423CrossRefGoogle ScholarPubMed
147Wahl, S. et al. (2000) Ephrin-A5 induces collapse of growth cones by activating Rho and Rho kinase. Journal of Cell Biology 149, 263-270CrossRefGoogle ScholarPubMed
148Sjoberg, J. and Kanje, M. (1990) Effects of repetitive conditioning crush lesions on regeneration of the rat sciatic nerve. Brain Research 530, 167-169CrossRefGoogle ScholarPubMed
149Gaete, J., Kameid, G. and Alvarez, J. (1998) Regenerating axons of the rat require a local source of proteins. Neuroscience Letters 251, 197-200CrossRefGoogle ScholarPubMed
150Verma, P. et al. (2005) Axonal protein synthesis and degradation are necessary for efficient growth cone regeneration. Journal of Neuroscience 25, 331-342CrossRefGoogle ScholarPubMed
151Twiss, J.L. and van Minnen, J. (2006) New insights into neuronal regeneration: the role of axonal protein synthesis in pathfinding and axonal extension. Journal of Neurotrauma 23, 295-308CrossRefGoogle ScholarPubMed
152Zheng, J.Q. et al. (2001) A functional role for intra-axonal protein synthesis during axonal regeneration from adult sensory neurons. Journal of Neuroscience 21, 9291-9303CrossRefGoogle ScholarPubMed
153Hanz, S. et al. (2003) Axoplasmic importins enable retrograde injury signaling in lesioned nerve. Neuron 40, 1095-1104CrossRefGoogle ScholarPubMed
154Guirland, C. et al. (2004) Lipid rafts mediate chemotropic guidance of nerve growth cones. Neuron 42, 51-62CrossRefGoogle ScholarPubMed
155Ledeen, R.W. et al. (1998) The role of GM1 and other gangliosides in neuronal differentiation. Overview and new finding. Annals of the New York Academy of Sciences 845, 161-175CrossRefGoogle ScholarPubMed
156Harel, R. and Futerman, A.H. (1993) Inhibition of sphingolipid synthesis affects axonal outgrowth in cultured hippocampal neurons. Journal of Biological Chemistry 268, 14476-14481CrossRefGoogle ScholarPubMed
157Vyas, A.A. et al. (2002) Gangliosides are functional nerve cell ligands for myelin-associated glycoprotein (MAG), an inhibitor of nerve regeneration. Proceedings of the National Academy of Sciences of the United States of America 99, 8412-8417CrossRefGoogle ScholarPubMed
158Yang, L.J. et al. (2006) Sialidase enhances spinal axon outgrowth in vivo. Proceedings of the National Academy of Sciences of the United States of America 103, 11057-11062CrossRefGoogle ScholarPubMed
159Wu, G., Nakamura, K. and Ledeen, R.W. (1994) Inhibition of neurite outgrowth of neuroblastoma Neuro-2a cells by cholera toxin B-subunit and anti-GM1 antibody. Molecular and Chemical Neuropathology 21, 259-271CrossRefGoogle ScholarPubMed
160Spirman, N. et al. (1984) Regenerative capacity of the goldfish visual system is affected by antibodies specific to gangliosides injected intraocularly. Journal of Neuroimmunology 6, 197-207CrossRefGoogle ScholarPubMed
161Ferrari, G. et al. (1995) Prevention of apoptotic neuronal death by GM1 ganglioside. Involvement of Trk neurotrophin receptors. Journal of Biological Chemistry 270, 3074-3080CrossRefGoogle ScholarPubMed
162Rybak, S., Ginzburg, I. and Yavin, E. (1983) Gangliosides stimulate neurite outgrowth and induce tubulin mRNA accumulation in neural cells. Biochemical and Biophysical Research Communications 116, 974-980CrossRefGoogle ScholarPubMed
163Schneider, J.S., Schroeder, J.A. and Rothblat, D.S. (1998) Differential recovery of sensorimotor function in GM1 ganglioside-treated vs. spontaneously recovered MPTP-treated cats: partial striatal dopaminergic reinnervation vs. neurochemical compensation. Brain Research 813, 82-87CrossRefGoogle ScholarPubMed
164Geisler, F.H. et al. (2001) The Sygen multicenter acute spinal cord injury study. Spine 26, S87-98CrossRefGoogle ScholarPubMed
165Riboni, L. et al. (1990) Patterns of endogenous gangliosides and metabolic processing of exogenous gangliosides in cerebellar granule cells during differentiation in culture. Neurochemical Research 15, 1175-1183CrossRefGoogle ScholarPubMed
166Neugebauer, K.M. and Reichardt, L.F. (1991) Cell-surface regulation of beta 1-integrin activity on developing retinal neurons. Nature 350, 68-71CrossRefGoogle ScholarPubMed
167Lemons, M.L. and Condic, M.L. (2006) Combined integrin activation and intracellular cAMP cause Rho GTPase dependent growth cone collapse on laminin-1. Experimental Neurology 202, 324-335CrossRefGoogle ScholarPubMed
168Yanagida, H., Tanaka, J. and Maruo, S. (1999) Immunocytochemical localization of a cell adhesion molecule, integrin alpha5beta1, in nerve growth cones. Journal of Orthopaedic Science 4, 353-360CrossRefGoogle ScholarPubMed
169Wallquist, W. et al. (2004) Dorsal root ganglion neurons up-regulate the expression of laminin-associated integrins after peripheral but not central axotomy. Journal of Comparative Neurology 480, 162-169CrossRefGoogle Scholar
170Gardiner, N.J. et al. (2005) Alpha7 integrin mediates neurite outgrowth of distinct populations of adult sensory neurons. Molecular and Cellular Neurosciences 28, 229-240CrossRefGoogle ScholarPubMed
171Ekstrom, P.A. et al. (2003) Involvement of alpha7beta1 integrin in the conditioning-lesion effect on sensory axon regeneration. Molecular and Cellular Neurosciences 22, 383-395CrossRefGoogle ScholarPubMed
172Plantman, S. et al. (2005) Integrin messenger RNAs in the red nucleus after axotomy and neurotrophic administration. Neuroreport 16, 709-713CrossRefGoogle ScholarPubMed
173Andrews, M.R. et al. (2009) Alpha9 integrin promotes neurite outgrowth on tenascin-C and enhances sensory axon regeneration. Journal of Neuroscience 29, 5546-5557CrossRefGoogle ScholarPubMed

Further reading, resources and contacts

For the latest updates on research on spinal cord injury and clinical trials see the website of the NIH National Institute of Neurological Disorders:

http://www.ninds.nih.gov/disorders

Silver, J. and Miller, J.H. (2004) Regeneration beyond the glial scar. Nature Reviews Neuroscience 5, 146-156CrossRefGoogle ScholarPubMed
Rolls, A., Shechter, R. and Schwartz, M. (2009) The bright side of the glial scar in CNS repair. Nature Reviews Neuroscience 10, 235-241CrossRefGoogle ScholarPubMed
Cafferty, W.B., McGee, A.W. and Strittmatter, S.M. (2008) Axonal growth therapeutics: regeneration or sprouting or plasticity? Trends in Neurosciences 31, 215-220CrossRefGoogle ScholarPubMed
Silver, J. and Miller, J.H. (2004) Regeneration beyond the glial scar. Nature Reviews Neuroscience 5, 146-156CrossRefGoogle ScholarPubMed
Rolls, A., Shechter, R. and Schwartz, M. (2009) The bright side of the glial scar in CNS repair. Nature Reviews Neuroscience 10, 235-241CrossRefGoogle ScholarPubMed
Cafferty, W.B., McGee, A.W. and Strittmatter, S.M. (2008) Axonal growth therapeutics: regeneration or sprouting or plasticity? Trends in Neurosciences 31, 215-220CrossRefGoogle ScholarPubMed