Journal of Molecular Medicine

, Volume 83, Issue 9, pp 657–671

Molecular targets in spinal cord injury

Review

Abstract

The spinal cord can be compared to a highway connecting the brain with the different body levels lying underneath, with the axons being the ultimate carriers of the electrical impulse. After spinal cord injury (SCI), many cells are lost because of the injury. To reconstitute function, damaged axons from surviving neurons have to grow through the lesion site to their initial targets. However, the territory they have to traverse has changed: the highway is full of inhibitory signals (myelin and scar components); the pavement itself has become bumpy (demyelination); and specialized cells are recruited to clear the way (inflammatory cells). Thus, actual strategies to treat spinal injuries aim at providing a permissive environment for regenerating axons and boosting the endogenous potential of axons to regenerate while limiting progression of secondary damage. Here we review some of the strategies currently under consideration to treat spinal injuries.

Keywords

Spinal trauma Neuroprotective strategies Molecular targets Apoptosis Myelin Concomitant function 

Abbreviations

SCI

Spinal cord injury

ATP

Adenosine triphosphate

NMDA

N-methyl-d-aspartate

AMPA

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

NASCIS

National Acute Spinal Cord Injury Study

NO

Nitric oxide

NOS

Nitric oxide synthase

4-AP

4-Aminopyridine

MP

Methylprednisolone

MMP

Matrix metalloprotease

ICAM-1

Intercellular adhesion molecule-1

VCAM-1

Vascular cell adhesion molecule-1

TNF

Tumor necrosis factor

IL

Interleukin

PG

Prostaglandin

COX

Cyclooxygenase

MBP

Myelin basic protein

zVAD-fmk

N-Benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone

p75NTR

p75 neurotrophin receptor

CD95L

CD95 ligand

BBB

Blood–brain barrier

CSPGs

Chondroitin sulfate proteoglycans

OMgp

Oligodendrocyte myelin glycoprotein

MAG

Myelin-associated glycoprotein

NgR

Nogo receptor

ROCK

RhoA-associated kinase

OECs

Olfactory ensheathing cells

OPCs

Oligodendrocyte precursor cells

MS

Multiple sclerosis

DRG

Dorsal root ganglion

cAMP

Cyclic adenosine monophosphate

PKA

Protein kinase-A

BDNF

Brain-derived neurotrophic factor

References

  1. 1.
    Wang X, Arcuino G, Takano T, Lin J, Peng WG, Wan P, Li P, Xu Q, Liu QS, Goldman SA, Nedergaard M (2004) P2X7 receptor inhibition improves recovery after spinal cord injury. Nat Med 10(8):821–827CrossRefPubMedGoogle Scholar
  2. 2.
    Cassada DC, Tribble CG, Young JS, Gangemi JJ, Gohari AR, Butler PD, Rieger JM, Kron IL, Linden J, Kern JA (2002) Adenosine A2A analogue improves neurologic outcome after spinal cord trauma in the rabbit. J Trauma 53(2):225–229PubMedGoogle Scholar
  3. 3.
    Rosenberg LJ, Teng YD, Wrathall JR (1999) Effects of the sodium channel blocker tetrodotoxin on acute white matter pathology after experimental contusive spinal cord injury. J Neurosci 19(14):6122–6133PubMedGoogle Scholar
  4. 4.
    Schwartz G, Fehlings MG (2001) Evaluation of the neuroprotective effects of sodium channel blockers after spinal cord injury: improved behavioral and neuroanatomical recovery with riluzole. J Neurosurg Spine 94(2):245–256Google Scholar
  5. 5.
    Hulsebosch CE (2002) Recent advances in pathophysiology and treatment of spinal cord injury. Adv Physiol Educ 26(1–4):238–255PubMedGoogle Scholar
  6. 6.
    Feldblum S, Arnaud S, Simon M, Rabin O, D’Arbigny P (2000) Efficacy of a new neuroprotective agent, gacyclidine, in a model of rat spinal cord injury. J Neurotrauma 17(11):1079–1093PubMedGoogle Scholar
  7. 7.
    Mitha AP, Maynard KI (2001) Gacyclidine (Beaufour-Ipsen). Curr Opin Investig Drugs 2(6):814–819PubMedGoogle Scholar
  8. 8.
    Benzel EC, Khare V, Fowler MR (1992) Effects of naloxone and nalmefene in rat spinal cord injury induced by the ventral compression technique. J Spinal Disord 5(1):75–77PubMedGoogle Scholar
  9. 9.
    Wrathall JR, Choiniere D, Teng YD (1994) Dose-dependent reduction of tissue loss and functional impairment after spinal cord trauma with the AMPA/kainate antagonist NBQX. J Neurosci 14(11 Pt 1):6598–6607PubMedGoogle Scholar
  10. 10.
    Bracken MB, Shepard MJ, Collins WF, Holford TR, Young W, Baskin DS, Eisenberg HM, Flamm E, Leo-Summers L, Maroon J (1990) A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal-cord injury. Results of the Second National Acute Spinal Cord Injury Study. N Engl J Med 322(20):1405–1411PubMedGoogle Scholar
  11. 11.
    Farooqui AA, Horrocks LA (1998) Lipid peroxides in the free radical pathophysiology of brain diseases. Cell Mol Neurobiol 18(6):599–608CrossRefPubMedGoogle Scholar
  12. 12.
    Nakauchi K, Ikata T, Katoh S, Hamada Y, Tsuchiya K, Fukuzawa K (1996) Effects of lecithinized superoxide dismutase on rat spinal cord injury. J Neurotrauma 13(10):573–582PubMedGoogle Scholar
  13. 13.
    Sugawara T, Lewen A, Gasche Y, Yu F, Chan PH (2002) Overexpression of SOD1 protects vulnerable motor neurons after spinal cord injury by attenuating mitochondrial cytochrome c release. FASEB J 16(14):1997–1999PubMedGoogle Scholar
  14. 14.
    Farooque M, Isaksson J, Olsson Y (2001) Improved recovery after spinal cord injury in neuronal nitric oxide synthase-deficient mice but not in TNF-alpha-deficient mice. J Neurotrauma 18(1):105–114CrossRefPubMedGoogle Scholar
  15. 15.
    Pearse DD, Chatzipanteli K, Marcillo AE, Bunge MB, Dietrich WD (2003) Comparison of INOS inhibition by antisense and pharmacological inhibitors after spinal cord injury. J Neuropathol Exp Neurol 62(11):1096–1107PubMedGoogle Scholar
  16. 16.
    Yuceer N, Tuna H, Attar A, Sargon MF, Egemen N (2002) The effects of topical l-arginine and Ng-nitro-l-arginine methyl ester after experimental acute spinal cord injury. A light and electron microscopic study. Neurosurg Rev 25(3):184–190CrossRefPubMedGoogle Scholar
  17. 17.
    Bozbuga M, Izgi N, Canbolat A (1998) The effects of chronic alpha-tocopherol administration on lipid peroxidation in an experimental model of acute spinal cord injury. Neurosurg Rev 21(1):36–42CrossRefPubMedGoogle Scholar
  18. 18.
    Fujimoto T, Nakamura T, Ikeda T, Takagi K (2000) Potent protective effects of melatonin on experimental spinal cord injury. Spine 25(7):769–775CrossRefPubMedGoogle Scholar
  19. 19.
    Fujimoto T, Nakamura T, Ikeda T, Taoka Y, Takagi K (2000) Effects of EPC-K1 on lipid peroxidation in experimental spinal cord injury. Spine 25(1):24–29CrossRefPubMedGoogle Scholar
  20. 20.
    Hall ED, Yonkers PA, Andrus PK, Cox JW, Anderson DK (1992) Biochemistry and pharmacology of lipid antioxidants in acute brain and spinal cord injury. J Neurotrauma 9(Suppl 2):S425–S442PubMedGoogle Scholar
  21. 21.
    Chang RC, Rota C, Glover RE, Mason RP, Hong JS (2000) A novel effect of an opioid receptor antagonist, naloxone, on the production of reactive oxygen species by microglia: a study by electron paramagnetic resonance spectroscopy. Brain Res 854(1–2):224–229CrossRefPubMedGoogle Scholar
  22. 22.
    Diaz-Ruiz A, Rios C, Duarte I, Correa D, Guizar-Sahagun G, Grijalva I, Ibarra A (1999) Cyclosporin-A inhibits lipid peroxidation after spinal cord injury in rats. Neurosci Lett 266(1):61–64CrossRefPubMedGoogle Scholar
  23. 23.
    Gorgulu A, Kiris T, Unal F, Turkoglu U, Kucuk M, Cobanoglu S (2000) Superoxide dismutase activity and the effects of NBQX and CPP on lipid peroxidation in experimental spinal cord injury. Res Exp Med (Berl) 199(5):285–293CrossRefGoogle Scholar
  24. 24.
    Haghighi SS, Clapper A, Johnson GC, Stevens A, Prapaisilp A (1998) Effect of 4-aminopyridine and single-dose methylprednisolone on functional recovery after a chronic spinal cord injury. Spinal Cord 36(1):6–12CrossRefPubMedGoogle Scholar
  25. 25.
    Hall ED (1992) The neuroprotective pharmacology of methylprednisolone. J Neurosurg 76(1):13–22PubMedGoogle Scholar
  26. 26.
    Rabchevsky AG, Fugaccia I, Sullivan PG, Blades DA, Scheff SW (2002) Efficacy of methylprednisolone therapy for the injured rat spinal cord. J Neurosci Res 68(1):7–18CrossRefPubMedGoogle Scholar
  27. 27.
    Takami T, Oudega M, Bethea JR, Wood PM, Kleitman N, Bunge MB (2002) Methylprednisolone and interleukin-10 reduce gray matter damage in the contused Fischer rat thoracic spinal cord but do not improve functional outcome. J Neurotrauma 19(5):653–666CrossRefPubMedGoogle Scholar
  28. 28.
    Wells JE, Hurlbert RJ, Fehlings MG, Yong VW (2003) Neuroprotection by minocycline facilitates significant recovery from spinal cord injury in mice. Brain 126(Pt 7):1628–1637CrossRefPubMedGoogle Scholar
  29. 29.
    Bracken MB, Shepard MJ, Collins WF Jr, Holford TR, Baskin DS, Eisenberg HM, Flamm E, Leo-Summers L, Maroon JC, Marshall LF (1992) Methylprednisolone or naloxone treatment after acute spinal cord injury: 1-year follow-up data. Results of the Second National Acute Spinal Cord Injury Study. J Neurosurg 76(1):23–31PubMedGoogle Scholar
  30. 30.
    Bracken MB, Shepard MJ, Holford TR, Leo-Summers L, Aldrich EF, Fazl M, Fehlings M, Herr DL, Hitchon PW, Marshall LF, Nockels RP, Pascale V, Perot PL Jr, Piepmeier J, Sonntag VK, Wagner F, Wilberger JE, Winn HR, Young W (1997) 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 277(20):1597–1604CrossRefPubMedGoogle Scholar
  31. 31.
    Bracken MB, Shepard MJ, Holford TR, Leo-Summers L, Aldrich EF, Fazl M, Fehlings MG, Herr DL, Hitchon PW, Marshall LF, Nockels RP, Pascale V, Perot PL Jr, Piepmeier J, Sonntag VK, Wagner F, Wilberger JE, Winn HR, Young W (1998) Methylprednisolone or tirilazad mesylate administration after acute spinal cord injury: 1-year follow up. Results of the Third National Acute Spinal Cord Injury Randomized Controlled Trial. J Neurosurg 89(5):699–706PubMedGoogle Scholar
  32. 32.
    Hurlbert RJ (2001) The role of steroids in acute spinal cord injury: an evidence-based analysis. Spine 26(24 Suppl):S39–S46CrossRefPubMedGoogle Scholar
  33. 33.
    Nesathurai S (1998) Steroids and spinal cord injury: revisiting the NASCIS 2 and NASCIS 3 trials. J Trauma 45(6):1088–1093PubMedGoogle Scholar
  34. 34.
    Sapolsky RM (1996) Stress, glucocorticoids, and damage to the nervous system: the current state of confusion. Stress 1(1):1–19PubMedGoogle Scholar
  35. 35.
    Guth L, Zhang Z, Roberts E (1994) Key role for pregnenolone in combination therapy that promotes recovery after spinal cord injury. Proc Natl Acad Sci U S A 91(25):12308–12312PubMedGoogle Scholar
  36. 36.
    Sribnick EA, Wingrave JM, Matzelle DD, Ray SK, Banik NL (2003) Estrogen as a neuroprotective agent in the treatment of spinal cord injury. Ann N Y Acad Sci 993:125–133PubMedGoogle Scholar
  37. 37.
    Thomas AJ, Nockels RP, Pan HQ, Shaffrey CI, Chopp M (1999) Progesterone is neuroprotective after acute experimental spinal cord trauma in rats. Spine 24(20):2134–2138CrossRefPubMedGoogle Scholar
  38. 38.
    Yong VW, Power C, Forsyth P, Edwards DR (2001) Metalloproteinases in biology and pathology of the nervous system. Nat Rev Neurosci 2(7):502–511CrossRefPubMedGoogle Scholar
  39. 39.
    Lee SR, Lo EH (2004) Induction of caspase-mediated cell death by matrix metalloproteinases in cerebral endothelial cells after hypoxia–reoxygenation. J Cereb Blood Flow Metab 24(7):720–727CrossRefPubMedGoogle Scholar
  40. 40.
    Noble LJ, Donovan F, Igarashi T, Goussev S, Werb Z (2002) Matrix metalloproteinases limit functional recovery after spinal cord injury by modulation of early vascular events. J Neurosci 22(17):7526–7535PubMedGoogle Scholar
  41. 41.
    Wells JE, Rice TK, Nuttall RK, Edwards DR, Zekki H, Rivest S, Yong VW (2003) An adverse role for matrix metalloproteinase 12 after spinal cord injury in mice. J Neurosci 23(31):10107–10115PubMedGoogle Scholar
  42. 42.
    Bevilacqua MP (1993) Endothelial-leukocyte adhesion molecules. Annu Rev Immunol 11:767–804CrossRefPubMedGoogle Scholar
  43. 43.
    Hynes RO (1992) Integrins: versatility, modulation, and signaling in cell adhesion. Cell 69(1):11–25CrossRefPubMedGoogle Scholar
  44. 44.
    Farooque M, Isaksson J, Olsson Y (1999) Improved recovery after spinal cord trauma in ICAM-1 and P-selectin knockout mice. Neuroreport 10(1):131–134PubMedGoogle Scholar
  45. 45.
    Hamada Y, Ikata T, Katoh S, Nakauchi K, Niwa M, Kawai Y, Fukuzawa K (1996) Involvement of an intercellular adhesion molecule 1-dependent pathway in the pathogenesis of secondary changes after spinal cord injury in rats. J Neurochem 66(4):1525–1531PubMedGoogle Scholar
  46. 46.
    Taoka Y, Okajima K, Uchiba M, Murakami K, Kushimoto S, Johno M, Naruo M, Okabe H, Takatsuki K (1997) Role of neutrophils in spinal cord injury in the rat. Neuroscience 79(4):1177–1182CrossRefPubMedGoogle Scholar
  47. 47.
    Gris D, Marsh DR, Oatway MA, Chen Y, Hamilton EF, Dekaban GA, Weaver LC (2004) Transient blockade of the CD11d/CD18 integrin reduces secondary damage after spinal cord injury, improving sensory, autonomic, and motor function. J Neurosci 24(16):4043–4051CrossRefPubMedGoogle Scholar
  48. 48.
    Yang L, Blumbergs PC, Jones NR, Manavis J, Sarvestani GT, Ghabriel MN (2004) Early expression and cellular localization of proinflammatory cytokines interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha in human traumatic spinal cord injury. Spine 29(9):966–971CrossRefPubMedGoogle Scholar
  49. 49.
    Martin-Villalba A, Hahne M, Kleber S, Vogel J, Falk W, Schenkel J, Krammer PH (2001) Therapeutic neutralization of CD95L and TNF attentuates brain damage in stroke. Cell Death Differ 8:679–686CrossRefPubMedGoogle Scholar
  50. 50.
    Demjen D, Klussmann S, Kleber S, Zuliani C, Stieltjes B, Metzger C, Hirt UA, Walczak H, Falk W, Essig M, Edler L, Krammer PH, Martin-Villalba A (2004) Neutralization of CD95 ligand promotes regeneration and functional recovery after spinal cord injury. Nat Med 10(4):389–395CrossRefPubMedGoogle Scholar
  51. 51.
    Nesic O, Xu GY, McAdoo D, High KW, Hulsebosch C, Perez-Pol R (2001) IL-1 receptor antagonist prevents apoptosis and caspase-3 activation after spinal cord injury. J Neurotrauma 18(9):947–956PubMedGoogle Scholar
  52. 52.
    Bethea JR, Nagashima H, Acosta MC, Briceno C, Gomez F, Marcillo AE, Loor K, Green J, Dietrich WD (1999) Systemically administered interleukin-10 reduces tumor necrosis factor-alpha production and significantly improves functional recovery following traumatic spinal cord injury in rats. J Neurotrauma 16(10):851–863PubMedGoogle Scholar
  53. 53.
    Ghirnikar RS, Lee YL, Eng LF (2000) Chemokine antagonist infusion attenuates cellular infiltration following spinal cord contusion injury in rat. J Neurosci Res 59(1):63–73CrossRefPubMedGoogle Scholar
  54. 54.
    Hains BC, Yucra JA, Hulsebosch CE (2001) Reduction of pathological and behavioral deficits following spinal cord contusion injury with the selective cyclooxygenase-2 inhibitor NS-398. J Neurotrauma 18(4):409–423CrossRefPubMedGoogle Scholar
  55. 55.
    Resnick DK, Graham SH, Dixon CE, Marion DW (1998) Role of cyclooxygenase 2 in acute spinal cord injury. J Neurotrauma 15(12):1005–1013PubMedGoogle Scholar
  56. 56.
    Yamamoto T, Nozaki-Taguchi N (1996) Analysis of the effects of cyclooxygenase (COX)-1 and COX-2 in spinal nociceptive transmission using indomethacin, a non-selective COX inhibitor, and NS-398, a COX-2 selective inhibitor. Brain Res 739(1–2):104–110CrossRefPubMedGoogle Scholar
  57. 57.
    Rappert A, Bechmann I, Pivneva T, Mahlo J, Biber K, Nolte C, Kovac AD, Gerard C, Boddeke HW, Nitsch R, Kettenmann H (2004) CXCR3-dependent microglial recruitment is essential for dendrite loss after brain lesion. J Neurosci 24(39):8500–8509CrossRefPubMedGoogle Scholar
  58. 58.
    Hammarberg H, Lidman O, Lundberg C, Eltayeb SY, Gielen AW, Muhallab S, Svenningsson A, Linda H, Der Meide PH, Cullheim S, Olsson T, Piehl F (2000) Neuroprotection by encephalomyelitis: rescue of mechanically injured neurons and neurotrophin production by CNS-infiltrating T and natural killer cells. J Neurosci 20(14):5283–5291PubMedGoogle Scholar
  59. 59.
    Moalem G, Gdalyahu A, Shani Y, Otten U, Lazarovici P, Cohen IR, Schwartz M (2000) Production of neurotrophins by activated T cells: implications for neuroprotective autoimmunity. J Autoimmun 15(3):331–345CrossRefPubMedGoogle Scholar
  60. 60.
    Hauben E, Butovsky O, Nevo U, Yoles E, Moalem G, Agranov E, Mor F, Leibowitz-Amit R, Pevsner E, Akselrod S, Neeman M, Cohen IR, Schwartz M (2000) Passive or active immunization with myelin basic protein promotes recovery from spinal cord contusion. J Neurosci 20(17):6421–6430PubMedGoogle Scholar
  61. 61.
    Hauben E, Ibarra A, Mizrahi T, Barouch R, Agranov E, Schwartz M (2001) Vaccination with a Nogo-A-derived peptide after incomplete spinal-cord injury promotes recovery via a T-cell-mediated neuroprotective response: comparison with other myelin antigens. Proc Natl Acad Sci U S A 98(26):15173–15178CrossRefPubMedGoogle Scholar
  62. 62.
    Kipnis J, Mizrahi T, Hauben E, Shaked I, Shevach E, Schwartz M (2002) Neuroprotective autoimmunity: naturally occurring CD4+CD25+ regulatory T cells suppress the ability to withstand injury to the central nervous system. Proc Natl Acad Sci U S A 99(24):15620–15625CrossRefPubMedGoogle Scholar
  63. 63.
    Katoh K, Ikata T, Katoh S, Hamada Y, Nakauchi K, Sano T, Niwa M (1996) Induction and its spread of apoptosis in rat spinal cord after mechanical trauma. Neurosci Lett 216(1):9–12CrossRefPubMedGoogle Scholar
  64. 64.
    Li GL, Brodin G, Farooque M, Funa K, Holtz A, Wang WL, Olsson Y (1996) Apoptosis and expression of Bcl-2 after compression trauma to rat spinal cord. J Neuropathol Exp Neurol 55(3):280–289PubMedGoogle Scholar
  65. 65.
    Liu XZ, Xu XM, Hu R, Du C, Zhang SX, Mcdonald JW, Dong HX, Wu YJ, Fan GS, Jacquin MF, Hsu CY, Choi DW (1997) Neuronal and glial apoptosis after traumatic spinal cord injury. J Neurosci 17(14):5395–5406PubMedGoogle Scholar
  66. 66.
    Shuman SL, Bresnahan JC, Beattie MS (1997) Apoptosis of microglia and oligodendrocytes after spinal cord contusion in rats. J Neurosci Res 50(5):798–808CrossRefPubMedGoogle Scholar
  67. 67.
    Crowe MJ, Bresnahan JC, Shuman SL, Masters JN, Beattie MS (1997) Apoptosis and delayed degeneration after spinal cord injury in rats and monkeys. Nat Med 3(1):73–76CrossRefPubMedGoogle Scholar
  68. 68.
    Emery E, Aldana P, Bunge MB, Puckett W, Srinivasan A, Keane RW, Bethea J, Levi AD (1998) Apoptosis after traumatic human spinal cord injury. J Neurosurg 89(6):911–920PubMedGoogle Scholar
  69. 69.
    Hains BC, Black JA, Waxman SG (2003) Primary cortical motor neurons undergo apoptosis after axotomizing spinal cord injury. J Comp Neurol 462(3):328–341CrossRefPubMedGoogle Scholar
  70. 70.
    Lee BH, Lee KH, Kim UJ, Yoon do H, Sohn JH, Choi SS, Yi IG, Park YG (2004) Injury in the spinal cord may produce cell death in the brain. Brain Res 1020(1–2):37–44CrossRefPubMedGoogle Scholar
  71. 71.
    Li GL, Farooque M, Holtz A, Olsson Y (1999) Apoptosis of oligodendrocytes occurs for long distances away from the primary injury after compression trauma to rat spinal cord. Acta Neuropathol (Berl) 98(5):473–480CrossRefGoogle Scholar
  72. 72.
    Springer JE, Azbill RD, Knapp PE (1999) Activation of the caspase-3 apoptotic cascade in traumatic spinal cord injury. Nat Med 5(8):943–946CrossRefPubMedGoogle Scholar
  73. 73.
    Nicholson DW (2000) From bench to clinic with apoptosis-based therapeutic agents. Nature 407(6805):810–816CrossRefPubMedGoogle Scholar
  74. 74.
    Li M, Ona VO, Chen M, Kaul M, Tenneti L, Zhang X, Stieg PE, Lipton SA, Friedlander RM (2000) Functional role and therapeutic implications of neuronal caspase-1 and -3 in a mouse model of traumatic spinal cord injury. Neuroscience 99(2):333–342CrossRefPubMedGoogle Scholar
  75. 75.
    Ozawa H, Keane RW, Marcillo AE, Diaz PH, Dietrich WD (2002) Therapeutic strategies targeting caspase inhibition following spinal cord injury in rats. Exp Neurol 177(1):306–313CrossRefPubMedGoogle Scholar
  76. 76.
    Campbell DS, Holt CE (2003) Apoptotic pathway and MAPKs differentially regulate chemotropic responses of retinal growth cones. Neuron 37(6):939–952CrossRefPubMedGoogle Scholar
  77. 77.
    Ray SK, Hogan EL, Banik NL (2003) Calpain in the pathophysiology of spinal cord injury: neuroprotection with calpain inhibitors. Brain Res Brain Res Rev 42(2):169–185CrossRefPubMedGoogle Scholar
  78. 78.
    Schumacher PA, Siman RG, Fehlings MG (2000) Pretreatment with calpain inhibitor CEP-4143 inhibits calpain I activation and cytoskeletal degradation, improves neurological function, and enhances axonal survival after traumatic spinal cord injury. J Neurochem 74(4):1646–1655CrossRefPubMedGoogle Scholar
  79. 79.
    Yuan J, Yankner BA (2000) Apoptosis in the nervous system. Nature 407(6805):802–809CrossRefPubMedGoogle Scholar
  80. 80.
    Saavedra RA, Murray M, de Lacalle S, Tessler A (2000) In vivo neuroprotection of injured CNS neurons by a single injection of a DNA plasmid encoding the Bcl-2 gene. Prog Brain Res 128:365–372PubMedGoogle Scholar
  81. 81.
    Seki T, Hida K, Tada M, Koyanagi I, Iwasaki Y (2003) Role of the Bcl-2 gene after contusive spinal cord injury in mice. Neurosurgery 53(1):192–198CrossRefPubMedGoogle Scholar
  82. 82.
    Dong H, Fazzaro A, Xiang C, Korsmeyer SJ, Jacquin MF, Mcdonald JW (2003) Enhanced oligodendrocyte survival after spinal cord injury in Bax-deficient mice and mice with delayed wallerian degeneration. J Neurosci 23(25):8682–8691PubMedGoogle Scholar
  83. 83.
    Lee YB, Yune TY, Baik SY, Shin YH, Du S, Rhim H, Lee EB, Kim YC, Shin ML, Markelonis GJ, Oh TH (2000) Role of tumor necrosis factor-alpha in neuronal and glial apoptosis after spinal cord injury. Exp Neurol 166(1):190–195CrossRefPubMedGoogle Scholar
  84. 84.
    Kim GM, Xu J, Song SK, Yan P, Ku G, Xu XM, Hsu CY (2001) Tumor necrosis factor receptor deletion reduces nuclear factor-kappaB activation, cellular inhibitor of apoptosis protein 2 expression, and functional recovery after traumatic spinal cord injury. J Neurosci 21(17):6617–6625PubMedGoogle Scholar
  85. 85.
    Casha S, Yu WR, Fehlings MG (2001) Oligodendroglial apoptosis occurs along degenerating axons and is associated with FAS and P75 expression following spinal cord injury in the rat. Neuroscience 103(1):203–218CrossRefPubMedGoogle Scholar
  86. 86.
    Beattie MS, Harrington AW, Lee R, Kim JY, Boyce SL, Longo FM, Bresnahan JC, Hempstead BL, Yoon SO (2002) ProNGF induces P75-mediated death of oligodendrocytes following spinal cord injury. Neuron 36(3):375–386CrossRefPubMedGoogle Scholar
  87. 87.
    Kischkel FC, Hellbardt S, Behrmann I, Germer M, Pawlita M, Krammer PH, Peter ME (1995) Cytotoxicity-dependent APO-1 (Fas/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptor. EMBO J 14(22):5579–5588PubMedGoogle Scholar
  88. 88.
    Medema JP, Scaffidi C, Kischkel FC, Shevchenko A, Mann M, Krammer PH, Peter ME (1997) FLICE is activated by association with the CD95 death-inducing signaling complex (DISC). EMBO J 16(10):2794–2804PubMedGoogle Scholar
  89. 89.
    Yoshino O, Matsuno H, Nakamura H, Yudoh K, Abe Y, Sawai T, Uzuki M, Yonehara S, Kimura T (2004) The role of Fas-mediated apoptosis after traumatic spinal cord injury. Spine 29(13):1394–1404CrossRefPubMedGoogle Scholar
  90. 90.
    Yrjanheikki J, Tikka T, Keinanen R, Goldsteins G, Chan PH, Koistinaho J (1999) A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window. Proc Natl Acad Sci U S A 96(23):13496–13500CrossRefPubMedGoogle Scholar
  91. 91.
    Yrjanheikki J, Keinanen R, Pellikka M, Hokfelt T, Koistinaho J (1998) Tetracyclines inhibit microglial activation and are neuroprotective in global brain ischemia. Proc Natl Acad Sci U S A 95(26):15769–15774CrossRefPubMedGoogle Scholar
  92. 92.
    Chen M, Ona VO, Li M, Ferrante RJ, Fink KB, Zhu S, Bian J, Guo L, Farrell LA, Hersch SM, Hobbs W, Vonsattel JP, Cha JH, Friedlander RM (2000) Minocycline inhibits Caspase-1 and Caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease. Nat Med 6(7):797–801CrossRefPubMedGoogle Scholar
  93. 93.
    Teng YD, Choi H, Onario RC, Zhu S, Desilets FC, Lan S, Woodard EJ, Snyder EY, Eichler ME, Friedlander RM (2004) Minocycline inhibits contusion-triggered mitochondrial cytochrome c release and mitigates functional deficits after spinal cord injury. Proc Natl Acad Sci U S A 101(9):3071–3076CrossRefPubMedGoogle Scholar
  94. 94.
    Lee SM, Yune TY, Kim SJ, Park do W, Lee YK, Kim YC, Oh YJ, Markelonis GJ, Oh TH (2003) Minocycline reduces cell death and improves functional recovery after traumatic spinal cord injury in the rat. J Neurotrauma 20(10):1017–1027CrossRefPubMedGoogle Scholar
  95. 95.
    Stirling DP, Khodarahmi K, Liu J, McPhail LT, McBride CB, Steeves JD, Ramer MS, Tetzlaff W (2004) Minocycline treatment reduces delayed oligodendrocyte death, attenuates axonal dieback, and improves functional outcome after spinal cord injury. J Neurosci 24(9):2182–2190CrossRefPubMedGoogle Scholar
  96. 96.
    Sasaki R (2003) Pleiotropic functions of erythropoietin. Intern Med 42(2):142–149PubMedGoogle Scholar
  97. 97.
    Calapai G, Marciano MC, Corica F, Allegra A, Parisi A, Frisina N, Caputi AP, Buemi M (2000) Erythropoietin protects against brain ischemic injury by inhibition of nitric oxide formation. Eur J Pharmacol 401(3):349–356CrossRefPubMedGoogle Scholar
  98. 98.
    Kawakami M, Sekiguchi M, Sato K, Kozaki S, Takahashi M (2001) Erythropoietin receptor-mediated inhibition of exocytotic glutamate release confers neuroprotection during chemical ischemia. J Biol Chem 276(42):39469–39475CrossRefPubMedGoogle Scholar
  99. 99.
    Digicaylioglu M, Lipton SA (2001) Erythropoietin-mediated neuroprotection involves cross-talk between Jak2 and NF-kappaB signalling cascades. Nature 412(6847):641–647CrossRefPubMedGoogle Scholar
  100. 100.
    Villa P, Bigini P, Mennini T, Agnello D, Laragione T, Cagnotto A, Viviani B, Marinovich M, Cerami A, Coleman TR, Brines M, Ghezzi P (2003) Erythropoietin selectively attenuates cytokine production and inflammation in cerebral ischemia by targeting neuronal apoptosis. J Exp Med 198(6):971–975CrossRefPubMedGoogle Scholar
  101. 101.
    Shingo T, Sorokan ST, Shimazaki T, Weiss S (2001) Erythropoietin regulates the in vitro and in vivo production of neuronal progenitors by mammalian forebrain neural stem cells. J Neurosci 21(24):9733–9743PubMedGoogle Scholar
  102. 102.
    Ehrenreich H, Hasselblatt M, Dembowski C, Cepek L, Lewczuk P, Stiefel M, Rustenbeck HH, Breiter N, Jacob S, Knerlich F, Bohn M, Poser W, Ruther E, Kochen M, Gefeller O, Gleiter C, Wessel TC, De Ryck M, Itri L, Prange H, Cerami A, Brines M, Siren AL (2002) Erythropoietin therapy for acute stroke is both safe and beneficial. Mol Med 8(8):495–505PubMedGoogle Scholar
  103. 103.
    Gorio A, Gokmen N, Erbayraktar S, Yilmaz O, Madaschi L, Cichetti C, Di Giulio AM, Vardar E, Cerami A, Brines M (2002) Recombinant human erythropoietin counteracts secondary injury and markedly enhances neurological recovery from experimental spinal cord trauma. Proc Natl Acad Sci U S A 99(14):9450–9455CrossRefPubMedGoogle Scholar
  104. 104.
    Erbayraktar S, Grasso G, Sfacteria A, Xie QW, Coleman T, Kreilgaard M, Torup L, Sager T, Erbayraktar Z, Gokmen N, Yilmaz O, Ghezzi P, Villa P, Fratelli M, Casagrande S, Leist M, Helboe L, Gerwein J, Christensen S, Geist MA, Pedersen LO, Cerami-Hand C, Wuerth JP, Cerami A, Brines M (2003) Asialoerythropoietin is a nonerythropoietic cytokine with broad neuroprotective activity in vivo. Proc Natl Acad Sci U S A 100(11):6741–6746CrossRefPubMedGoogle Scholar
  105. 105.
    Leist M, Ghezzi P, Grasso G, Bianchi R, Villa P, Fratelli M, Savino C, Bianchi M, Nielsen J, Gerwien J, Kallunki P, Larsen AK, Helboe L, Christensen S, Pedersen LO, Nielsen M, Torup L, Sager T, Sfacteria A, Erbayraktar S, Erbayraktar Z, Gokmen N, Yilmaz O, Cerami-Hand C, Xie QW, Coleman T, Cerami A, Brines M (2004) Derivatives of erythropoietin that are tissue protective but not erythropoietic. Science 305(5681):239–242CrossRefPubMedGoogle Scholar
  106. 106.
    Silver J, Miller JH (2004) Regeneration beyond the glial scar. Nat Rev Neurosci 5(2):146–156CrossRefPubMedGoogle Scholar
  107. 107.
    He Z, Koprivica V (2004) The Nogo signaling pathway for regeneration block. Annu Rev Neurosci 27:341–368CrossRefPubMedGoogle Scholar
  108. 108.
    Bradbury EJ, Moon LD, Popat RJ, King VR, Bennett GS, Patel PN, Fawcett JW, McMahon SB (2002) Chondroitinase ABC promotes functional recovery after spinal cord injury. Nature 416(6881):636–640CrossRefPubMedGoogle Scholar
  109. 109.
    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. Bibl Anat (23):1–11Google Scholar
  110. 110.
    Cordes N (2004) Overexpression of hyperactive integrin-linked kinase leads to increased cellular radiosensitivity. Cancer Res 64(16):5683–5692PubMedGoogle Scholar
  111. 111.
    Caroni P, Schwab ME (1988) Two membrane protein fractions from rat central myelin with inhibitory properties for neurite growth and fibroblast spreading. J Cell Biol 106(4):1281–1288CrossRefPubMedGoogle Scholar
  112. 112.
    Caroni P, Schwab ME (1988) Antibody against myelin-associated inhibitor of neurite growth neutralizes nonpermissive substrate properties of CNS white matter. Neuron 1(1):85–96CrossRefPubMedGoogle Scholar
  113. 113.
    Schnell L, Schwab ME (1990) Axonal Regeneration in the rat spinal cord produced by an antibody against myelin-associated neurite growth inhibitors. Nature 343(6255):269–272CrossRefPubMedGoogle Scholar
  114. 114.
    Chen MS, Huber AB, van der Haar ME, Frank M, Schnell L, Spillmann AA, Christ F, Schwab ME (2000) Nogo-A is a myelin-associated neurite outgrowth inhibitor and an antigen for monoclonal antibody IN-1. Nature 403(6768):434–439CrossRefPubMedGoogle Scholar
  115. 115.
    GrandPre T, Nakamura F, Vartanian T, Strittmatter SM (2000) Identification of the Nogo inhibitor of axon regeneration as a reticulon protein. Nature 403(6768):439–444CrossRefPubMedGoogle Scholar
  116. 116.
    Prinjha R, Moore SE, Vinson M, Blake S, Morrow R, Christie G, Michalovich D, Simmons DL, Walsh FS (2000) Inhibitor of neurite outgrowth in humans. Nature 403(6768):383–384CrossRefPubMedGoogle Scholar
  117. 117.
    Schwab ME (2004) Nogo and axon regeneration. Curr Opin Neurobiol 14(1):118–124CrossRefPubMedGoogle Scholar
  118. 118.
    Kim JE, Li S, GrandPre T, Qiu D, Strittmatter SM (2003) Axon regeneration in young adult mice lacking Nogo-A/B. Neuron 38(2):187–199CrossRefPubMedGoogle Scholar
  119. 119.
    Simonen M, Pedersen V, Weinmann O, Schnell L, Buss A, Ledermann B, Christ F, Sansig G, van der Putten H, Schwab ME (2003) Systemic deletion of the myelin-associated outgrowth inhibitor Nogo-A improves regenerative and plastic responses after spinal cord injury. Neuron 38(2):201–211CrossRefPubMedGoogle Scholar
  120. 120.
    Zheng B, Ho C, Li S, Keirstead H, Steward O, Tessier-Lavigne M (2003) Lack of enhanced spinal regeneration in Nogo-deficient mice. Neuron 38(2):213–224CrossRefPubMedGoogle Scholar
  121. 121.
    Domeniconi M, Cao Z, Spencer T, Sivasankaran R, Wang K, Nikulina E, Kimura N, Cai H, Deng K, Gao Y, He Z, Filbin M (2002) Myelin-associated glycoprotein interacts with the Nogo66 receptor to inhibit neurite outgrowth. Neuron 35(2):283–290CrossRefPubMedGoogle Scholar
  122. 122.
    Fournier AE, GrandPre T, Strittmatter SM (2001) Identification of a receptor mediating Nogo-66 inhibition of axonal regeneration. Nature 409(6818):341–346CrossRefPubMedGoogle Scholar
  123. 123.
    Wang KC, Kim JA, Sivasankaran R, Segal R, He Z (2002) P75 Interacts with the Nogo receptor as a co-receptor for Nogo, MAG and OMgp. Nature 420(6911):74–78CrossRefPubMedGoogle Scholar
  124. 124.
    Yamashita T, Higuchi H, Tohyama M (2002) The P75 receptor transduces the signal from myelin-associated glycoprotein to rho. J Cell Biol 157(4):565–570CrossRefPubMedGoogle Scholar
  125. 125.
    Song XY, Zhong JH, Wang X, Zhou XF (2004) Suppression of P75NTR does not promote regeneration of injured spinal cord in mice. J Neurosci 24(2):542–546CrossRefPubMedGoogle Scholar
  126. 126.
    Dergham P, Ellezam B, Essagian C, Avedissian H, Lubell WD, McKerracher L (2002) Rho signaling pathway targeted to promote spinal cord repair. J Neurosci 22(15):6570–6577PubMedGoogle Scholar
  127. 127.
    Fournier AE, Takizawa BT, Strittmatter SM (2003) Rho kinase inhibition enhances axonal regeneration in the injured CNS. J Neurosci 23(4):1416–1423PubMedGoogle Scholar
  128. 128.
    Lehmann M, Fournier A, Selles-Navarro I, Dergham P, Sebok A, Leclerc N, Tigyi G, McKerracher L (1999) Inactivation of rho signaling pathway promotes CNS axon regeneration. J Neurosci 19(17):7537–7547PubMedGoogle Scholar
  129. 129.
    Moreau-Fauvarque C, Kumanogoh A, Camand E, Jaillard C, Barbin G, Boquet I, Love C, Jones EY, Kikutani H, Lubetzki C, Dusart I, Chedotal A (2003) The transmembrane semaphorin Sema4D/CD100, an inhibitor of axonal growth, is expressed on oligodendrocytes and upregulated after CNS lesion. J Neurosci 23(27):9229–9239PubMedGoogle Scholar
  130. 130.
    Swiercz JM, Kuner R, Behrens J, Offermanns S (2002) Plexin-B1 directly interacts with PDZ-RhoGEF/LARG to regulate rhoA and growth cone morphology. Neuron 35(1):51–63CrossRefPubMedGoogle Scholar
  131. 131.
    Rapalino O, Lazarov-Spiegler O, Agranov E, Velan GJ, Yoles E, Fraidakis M, Solomon A, Gepstein R, Katz A, Belkin M, Hadani M, Schwartz M (1998) Implantation of stimulated homologous macrophages results in partial recovery of paraplegic rats. Nat Med 4(7):814–821CrossRefPubMedGoogle Scholar
  132. 132.
    Hauben E, Gothilf A, Cohen A, Butovsky O, Nevo U, Smirnov I, Yoles E, Akselrod S, Schwartz M (2003) Vaccination with dendritic cells pulsed with peptides of myelin basic protein promotes functional recovery from spinal cord injury. J Neurosci 23(25):8808–8819PubMedGoogle Scholar
  133. 133.
    GrandPre T, Li S, Strittmatter SM (2002) Nogo-66 receptor antagonist peptide promotes axonal regeneration. Nature 417(6888):547–551CrossRefPubMedGoogle Scholar
  134. 134.
    Barnett SC, Riddell JS (2004) Olfactory Ensheathing Cells (OECs) and the treatment of CNS injury: advantages and possible caveats. J Anat 204(1):57–67CrossRefPubMedGoogle Scholar
  135. 135.
    Franklin RJ (2003) Remyelination by transplanted olfactory ensheathing cells. Anat Rec 271B(1):71–76CrossRefGoogle Scholar
  136. 136.
    Raisman G (2001) Olfactory ensheathing cells—another miracle cure for spinal cord injury? Nat Rev Neurosci 2(5):369–375CrossRefPubMedGoogle Scholar
  137. 137.
    Duncan ID, Aguayo AJ, Bunge RP, Wood PM (1981) Transplantation of rat schwann cells grown in tissue culture into the mouse spinal cord. J Neurol Sci 49(2):241–252CrossRefPubMedGoogle Scholar
  138. 138.
    Tuszynski MH, Weidner N, McCormack M, Miller I, Powell H, Conner J (1998) Grafts of genetically modified Schwann cells to the spinal cord: survival, axon growth, and myelination. Cell Transplant 7(2):187–196CrossRefPubMedGoogle Scholar
  139. 139.
    Barnett SC, Hutchins AM, Noble M (1993) Purification of olfactory nerve ensheathing cells from the olfactory bulb. Dev Biol 155(2):337–350CrossRefPubMedGoogle Scholar
  140. 140.
    Groves AK, Barnett SC, Franklin RJ, Crang AJ, Mayer M, Blakemore WF, Noble M (1993) Repair of demyelinated lesions by transplantation of purified O-2A progenitor cells. Nature 362(6419):453–455CrossRefPubMedGoogle Scholar
  141. 141.
    Campbell K, Gotz M (2002) Radial glia: multi-purpose cells for vertebrate brain development. Trends Neurosci 25(5):235–238CrossRefPubMedGoogle Scholar
  142. 142.
    Horner PJ, Gage FH (2000) Regenerating the damaged central nervous system. Nature 407(6807):963–970CrossRefPubMedGoogle Scholar
  143. 143.
    Li Y, Field PM, Raisman G (1997) Repair of adult rat corticospinal tract by transplants of olfactory ensheathing cells. Science 277(5334):2000–2002CrossRefPubMedGoogle Scholar
  144. 144.
    Ramon-Cueto A, Plant GW, Avila J, Bunge MB (1998) Long-distance axonal regeneration in the transected adult rat spinal cord is promoted by olfactory ensheathing glia transplants. J Neurosci 18(10):3803–3815PubMedGoogle Scholar
  145. 145.
    Li Y, Raisman G (1994) Schwann cells induce sprouting in motor and sensory axons in the adult rat spinal cord. J Neurosci 14(7):4050–4063PubMedGoogle Scholar
  146. 146.
    Li Y, Field PM, Raisman G (1998) Regeneration of adult rat corticospinal axons induced by transplanted olfactory ensheathing cells. J Neurosci 18(24):10514–10524PubMedGoogle Scholar
  147. 147.
    Blesch A, Lu P, Tuszynski MH (2002) Neurotrophic factors, gene therapy, and neural stem cells for spinal cord repair. Brain Res Bull 57(6):833–838CrossRefPubMedGoogle Scholar
  148. 148.
    Myckatyn TM, Mackinnon SE, Mcdonald JW (2004) Stem cell transplantation and other novel techniques for promoting recovery from spinal cord injury. Transpl Immunol 12(3–4):343–358CrossRefPubMedGoogle Scholar
  149. 149.
    Mcdonald JW, Liu XZ, Qu Y, Liu S, Mickey SK, Turetsky D, Gottlieb DI, Choi DW (1999) Transplanted embryonic stem cells survive, differentiate and promote recovery in injured rat spinal cord. Nat Med 5(12):1410–1412CrossRefPubMedGoogle Scholar
  150. 150.
    Mcdonald JW, Becker D (2003) Spinal cord injury: promising interventions and realistic goals. Am J Phys Med Rehabil 82(10 Suppl):S38–S49CrossRefPubMedGoogle Scholar
  151. 151.
    Ceccatelli S, Tamm C, Sleeper E, Orrenius S (2004) Neural stem cells and cell death. Toxicol Lett 149(1–3):59–66CrossRefPubMedGoogle Scholar
  152. 152.
    Johansson CB, Momma S, Clarke DL, Risling M, Lendahl U, Frisen J (1999) Identification of a neural stem cell in the adult mammalian central nervous system. Cell 96(1):25–34CrossRefPubMedGoogle Scholar
  153. 153.
    Shihabuddin LS, Horner PJ, Ray J, Gage FH (2000) Adult spinal cord stem cells generate neurons after transplantation in the adult dentate gyrus. J Neurosci 20(23):8727–8735PubMedGoogle Scholar
  154. 154.
    Hayes KC, Blight AR, Potter PJ, Allatt RD, Hsieh JT, Wolfe DL, Lam S, Hamilton JT (1993) Preclinical trial of 4-aminopyridine in patients with chronic spinal cord injury. Paraplegia 31(4):216–224PubMedGoogle Scholar
  155. 155.
    Warrington AE, Asakura K, Bieber AJ, Ciric B, Van, Keulen, V, Kaveri SV, Kyle RA, Pease LR, Rodriguez M (2000) Human monoclonal antibodies reactive to oligodendrocytes promote remyelination in a model of multiple sclerosis. Proc Natl Acad Sci U S A 97(12):6820–6825CrossRefPubMedGoogle Scholar
  156. 156.
    Cannella B, Hoban CJ, Gao YL, Garcia-Arenas R, Lawson D, Marchionni M, Gwynne D, Raine CS (1998) The neuregulin, glial growth factor 2, diminishes autoimmune demyelination and enhances remyelination in a chronic relapsing model for multiple sclerosis. Proc Natl Acad Sci U S A 95(17):10100–10105CrossRefPubMedGoogle Scholar
  157. 157.
    Cai D, Shen Y, De Bellard M, Tang S, Filbin MT (1999) Prior exposure to neurotrophins blocks inhibition of axonal regeneration by MAG and myelin via a CAMP-dependent mechanism. Neuron 22(1):89–101CrossRefPubMedGoogle Scholar
  158. 158.
    Qiu J, Cai D, Dai H, McAtee M, Hoffman PN, Bregman BS, Filbin MT (2002) Spinal axon regeneration induced by elevation of cyclic AMP. Neuron 34(6):895–903CrossRefPubMedGoogle Scholar
  159. 159.
    Spencer T, Filbin MT (2004) A role for CAMP in regeneration of the adult mammalian CNS. J Anat 204(1):49–55CrossRefPubMedGoogle Scholar
  160. 160.
    Nikulina E, Tidwell JL, Dai HN, Bregman BS, Filbin MT (2004) The phosphodiesterase inhibitor rolipram delivered after a spinal cord lesion promotes axonal regeneration and functional recovery. Proc Natl Acad Sci U S A 101(23):8786–8790CrossRefPubMedGoogle Scholar
  161. 161.
    Pearse DD, Pereira FC, Marcillo AE, Bates ML, Berrocal YA, Filbin MT, Bunge MB (2004) CAMP and schwann cells promote axonal growth and functional recovery after spinal cord injury. Nat Med 10(6):610–616CrossRefPubMedGoogle Scholar
  162. 162.
    Becker T, Wullimann MF, Becker CG, Bernhardt RR, Schachner M (1997) Axonal regrowth after spinal cord transection in adult zebrafish. J Comp Neurol 377(4):577–595CrossRefPubMedGoogle Scholar
  163. 163.
    Bhatt DH, Otto SJ, Depoister B, Fetcho JR (2004) Cyclic AMP-induced repair of zebrafish spinal circuits. Science 305(5681):254–258CrossRefPubMedGoogle Scholar
  164. 164.
    Clemens S, Hue G, Sawchuk M, Zhu H, Hochman S (2004) Effects of dopaminergics and distribution of dopamine D2-like receptors in the spinal cord of wild type and D3 knockout mice. Spinal Cord Symposium. Christopher Reeve Paralysis Foundation, Springfield, NJGoogle Scholar
  165. 165.
    Gu B, Olejar KJ, Reiter JP, Thor KB, Dolber PC (2004) Inhibition of bladder activity by 5-HT1 serotonin receptor agonists in cats with chronic spinal cord injury. J Pharmacol Exp TherGoogle Scholar
  166. 166.
    Baker-Herman TL, Fuller DD, Bavis RW, Zabka AG, Golder FJ, Doperalski NJ, Johnson RA, Watters JJ, Mitchell GS (2004) BDNF is necessary and sufficient for spinal respiratory plasticity following intermittent hypoxia. Nat Neurosci 7(1):48–55CrossRefPubMedGoogle Scholar
  167. 167.
    Bareyre FM, Kerschensteiner M, Raineteau O, Mettenleiter TC, Weinmann O, Schwab ME (2004) The injured spinal cord spontaneously forms a new intraspinal circuit in adult rats. Nat Neurosci 7(3):269–277CrossRefPubMedGoogle Scholar
  168. 168.
    Dietz V, Harkema SJ (2004) Locomotor activity in spinal cord-injured persons. J Appl Physiol 96(5):1954–1960CrossRefPubMedGoogle Scholar
  169. 169.
    Harkema S (2004) The effects of stand training on standing, stepping, and bone mineral density afer clinically complete spinal cord injury. Spinal Cord Symposium. Christopher Reeve Paralysis Foundation, Springfield, NJGoogle Scholar
  170. 170.
    Basu S, Aballa TC, Ferrell SM, Lynne CM, Brackett NL (2004) Inflammatory cytokine concentrations are elevated in seminal plasma of men with spinal cord injuries. J Androl 25(2):250–254PubMedGoogle Scholar
  171. 171.
    Yezierski RP (2000) Pain following spinal cord injury: pathophysiology and central mechanisms. Prog Brain Res 129:429–449PubMedGoogle Scholar
  172. 172.
    Drew GM, Siddall PJ, Duggan AW (2004) Mechanical allodynia following contusion injury of the rat spinal cord is associated with loss of GABAergic inhibition in the dorsal horn. Pain 109(3):379–388CrossRefPubMedGoogle Scholar
  173. 173.
    Liu J, Wolfe D, Hao S, Huang S, Glorioso JC, Mata M, Fink DJ (2004) Peripherally delivered glutamic acid decarboxylase gene therapy for spinal cord injury pain. Mol Ther 10(1):57–66CrossRefPubMedGoogle Scholar
  174. 174.
    Lindenlaub T, Teuteberg P, Hartung T, Sommer C (2000) Effects of neutralizing antibodies to TNF-alpha on pain-related behavior and nerve regeneration in mice with chronic constriction injury. Brain Res 866(1–2):15–22CrossRefPubMedGoogle Scholar
  175. 175.
    Fairbanks CA, Schreiber KL, Brewer KL, Yu CG, Stone LS, Kitto KF, Nguyen HO, Grocholski BM, Shoeman DW, Kehl LJ, Regunathan S, Reis DJ, Yezierski RP, Wilcox GL (2000) Agmatine reverses pain induced by inflammation, neuropathy, and spinal cord injury. Proc Natl Acad Sci U S A 97(19):10584–10589CrossRefPubMedGoogle Scholar
  176. 176.
    Yu CG, Marcillo AE, Fairbanks CA, Wilcox GL, Yezierski RP (2000) Agmatine improves locomotor function and reduces tissue damage following spinal cord injury. NeuroReport 11(14):3203–3207PubMedGoogle Scholar
  177. 177.
    Anderson KD (2004) Targeting recovery: priorities of the spinal cord-injured population. J Neurotrauma 21(10):1371–1383CrossRefPubMedGoogle Scholar
  178. 178.
    Bregman BS, Coumans JV, Dai HN, Kuhn PL, Lynskey J, McAtee M, Sandhu F (2002) Transplants and neurotrophic factors increase regeneration and recovery of function after spinal cord injury. Prog Brain Res 137:257–273PubMedGoogle Scholar
  179. 179.
    Lu P, Yang H, Jones LL, Filbin MT, Tuszynski MH (2004) Combinatorial therapy with neurotrophins and CAMP promotes axonal regeneration beyond sites of spinal cord injury. J Neurosci 24(28):6402–6409CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  1. 1.Tumorimmunology Program, Division of ImmunogeneticsGerman Cancer Research CenterHeidelbergGermany

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