Rat models of spinal cord injury: From pathology to potential therapies

DMM Disease Models and Mechanisms

Volumn 9, Issue 10, 2016, Pages 1125-1137

  Kjell, Jacob ^a   Olson, Lars ^b  

^a UNIVERSITY OF MUNICH   (Germany)

^b KAROLINSKA INSTITUTE   (Sweden)

Author keywords

Clinical trials; Rat; Regeneration; Repair; Spinal cord injury

Indexed keywords

ANIMAL MODEL; EXPERIMENTAL SPINAL CORD INJURY; HUMAN; MYELINATION; NONHUMAN; PRIORITY JOURNAL; RAT; REVIEW; SCAR FORMATION; SPINAL CORD ATROPHY; SPINAL CORD INJURY; SPINAL CORD REGENERATION; SUBSTITUTION THERAPY; WALKING; WHITE MATTER; ANIMAL; CLINICAL TRIAL (TOPIC); COMPLICATION; CONVALESCENCE; DISEASE MODEL; INFLAMMATION; NERVE REGENERATION; PATHOLOGY; PATHOPHYSIOLOGY;

ANIMALS; CLINICAL TRIALS AS TOPIC; DISEASE MODELS, ANIMAL; HUMANS; INFLAMMATION; NERVE REGENERATION; RATS; RECOVERY OF FUNCTION; SPINAL CORD INJURIES;

EID: 84994056900     PISSN: 17548403     EISSN: 17548411     Source Type: Journal    
DOI: 10.1242/dmm.025833     Document Type: Review

References (181)

1. Abrams, G. M. and Ganguly, K. (2015). Management of chronic spinal cord dysfunction. CONTINUUM: Lifelong Learn. Neurol. 21, 188-200.
2. Abrams, M.B., Nilsson, I., Lewandowski, S.A., Kjell, J., Codeluppi, S., Olson, L. and Eriksson, U. (2012). Imatinib enhances functional outcome after spinal cord injury. PLoS ONE 7, e38760.
3. Adzemovic, M. Z., Zeitelhofer, M., Eriksson, U., Olsson, T. and Nilsson, I. (2013). Imatinib Ameliorates neuroinflammation in a rat model of multiple sclerosis by enhancing blood-brain barrier integrity and by modulating the peripheral immune response. PLoS ONE 8, e56586.
4. Ahuja, C. S. and Fehlings, M. (2016). Concise review: bridging the gap: novel neuroregenerative and neuroprotective strategies in spinal cord injury. Stem Cells Transl. Med. 5, 914-924.
5. Anderson, M. A., and Burda, J. E., Ren, Y., Ao, Y., O'Shea, T. M., Kawaguchi, R., Coppola, G., Khakh, B. S., Deming, T.J. and Sofroniew, M.V. (2016). Astrocyte scar formation aids central nervous system axon regeneration. Nature 532, 195-200.
6. Angeli, C. A., and Edgerton, V. R., Gerasimenko, Y. P. and Harkema, S. J. (2014). Altering spinal cord excitability enables voluntary movements after chronic complete paralysis in humans. Brain 137, 1394-1409.
7. Bao, F., Chen, Y., Dekaban, G. A. and Weaver, L. C. (2004). An anti-CD11d integrin antibody reduces cyclooxygenase-2 expression and protein and DNA oxidation after spinal cord injury in rats. J. Neurochem. 90, 1194-1204.
8. Bardehle, S., Krüger, M., Buggenthin, F., Schwausch, J., Ninkovic, J., Clevers, H., and Snippert, H. J., Theis, F. J., Meyer-Luehmann, M., Bechmann, I. et al. (2013). Live imaging of astrocyte responses to acute injury reveals selective juxtavascular proliferation. Nat. Neurosci. 16, 580-586.
9. Barnabé-Heider, F., Göritz, C., Sabelström, H., Takebayashi, H., Pfrieger, F. W., Meletis, K. and Frisén, J. (2010). Origin of new glial cells in intact and injured adult spinal cord. Cell Stem Cell 7, 470-482.
10. Basso, D. M., Beattie, M. S. and Bresnahan, J. C. (1996). Graded histological and locomotor outcomes after spinal cord contusion using the NYU weight-drop device versus transection. Exp. Neurol. 139, 244-256.
11. Beattie, M. S., Farooqui, A. A. and Bresnahan, J. C. (2000). Review of current evidence for apoptosis after spinal cord injury. J. Neurotrauma 17, 915-925.
12. Beck, K. D., and Nguyen, H. X., Galvan, M. D., Salazar, D. L., Woodruff, T. M. and Anderson, A. J. (2010). Quantitative analysis of cellular inflammation after traumatic spinal cord injury: evidence for a multiphasic inflammatory response in the acute to chronic environment. Brain 133, 433-447.
13. Bennett, D.J., Gorassini, M., Fouad, K., Sanelli, L., Han, Y. and Cheng, J. (1999). Spasticity in rats with sacral spinal cord injury. J. Neurotrauma 16, 69-84.
14. Blight, A. R. (1983). Cellular morphology of chronic spinal cord injury in the cat: analysis of myelinated axons by line-sampling. Neuroscience 10, 521-543.
15. Blight, A.R. (1991). Morphometric analysis of a model ofspinal cord injury in guinea pigs, with behavioral evidence of delayed secondary pathology. J. Neurol. Sci. 103, 156-171.
16. Blight, A. R. (1992). Macrophages and inflammatory damage in spinal cord injury. J. Neurotrauma 1, 83-91.
17. Borgmann-Winter, K. E., Rawson, N. E., Wang, H.-Y., Wang, H., and Macdonald, M. L., Ozdener, M. H., Yee, K. K., Gomez, G., Xu, J., Bryant, B. et al. (2009). Human olfactory epithelial cells generated in vitro express diverse neuronal characteristics. Neuroscience 158, 642-653.
18. Bradbury, E. J., Moon, L. D. F., Popat, R. J., and King, V. R., Bennett, G. S., Patel, P. N., Fawcett, J. W. and McMahon, S. B. (2002). Chondroitinase ABC promotes functional recovery after spinal cord injury. Nature 416, 636-640.
19. Bruce, J. H., and Norenberg, M. D., Kraydieh, S., Puckett, W., Marcillo, A. and Dietrich, D. (2000). Schwannosis: role of gliosis and proteoglycan in human spinal cord injury. J. Neurotrauma 17, 781-788.
20. Bruce, J. C., Oatway, M. A. and Weaver, L. C. (2002). Chronic pain after clipcompression injury of the rat spinal cord. Exp. Neurol. 178, 33-48.
21. Bunge, M. B. (2016). Efficacy of Schwann Cell (SC) transplantation for spinal cord repair is improved with combinatorial strategies. J. Physiol. 594, 3533-3538.
22. Bunge, M. B., Bunge, R. P. and Ris, H. (1961). Ultrastructural study of remyelination in an experimental lesion in adult cat spinal cord. J. Biophys. Biochem. Cytol. 10, 67-94.
23. Bunge, R. P., and Puckett, W. R., Becerra, J. L., Marcillo, A. and Quencer, R. M. (1993). Observations on the pathology of human spinal cord injury. A review and classification of 22 new cases with details from a case of chronic cord compression with extensive focal demyelination. Adv. Neurol. 59, 75-89.
24. Bunge, R. P., Puckett, W. R. and Hiester, E. D. (1997). Observations on the pathology of several types of human spinal cord injury, with emphasis on the astrocyte response to penetrating injuries. Adv. Neurol. 72, 305-315.
25. Buss, A., and Brook, G. A., Kakulas, B., Martin, D., Franzen, R., Schoenen, J., Noth, J. and Schmitt, A. B. (2004). Gradual loss ofmyelin and formation ofan astrocytic scar during Wallerian degeneration in the human spinal cord. Brain 127, 34-44.
26. Buss, A., Pech, K., Kakulas, B. A., Martin, D., Schoenen, J., Noth, J. and Brook, G. A. (2007). Matrix metalloproteinases and their inhibitors in human traumatic spinal cord injury. BMC Neurol. 7, 17.
27. Buss, A., Pech, K., Kakulas, B. A., Martin, D., Schoenen, J., Noth, J. and Brook, G. A. (2009). NG2 and phosphacan are present in the astroglial scar after human traumatic spinal cord injury. BMC Neurol. 9, 32.
28. Byrnes, K. R., Fricke, S. T. and Faden, A. I. (2010). Neuropathological differences between rats and mice after spinal cord injury. J. Magnetic Resonance Imaging 32, 836-846.
29. Carhart, M. R., He, J., Herman, R., D'luzansky, S. and Willis, W. (2004). Epidural spinal-cord stimulation facilitates recovery of functional walking following incomplete spinal-cord injury. IEEE Trans. Neural Syst. Rehabil. Eng. 12, 32-42.
30. Carlson, G. D., Minato, Y., Okada, A., Gorden, C. D., and Warden, K. E., Barbeau, J. M., Biro, C. L., Bahnuik, E., Bohlman, H. H. and Lamanna, J.C. (1997). Early time-dependent decompression for spinal cord injury: vascular mechanisms of recovery. J. Neurotrauma 14, 951-962.
31. Chaplan, S. R., and Bach, F. W., Pogrel, J. W., Chung, J. M. and Yaksh, T. L. (1994). Quantitative assessment of tactile allodynia in the rat paw. J. Neurosci. Methods 53, 55-63.
32. Cheng, H., Cao, Y. and Olson, L. (1996). Spinal cord repair in adult paraplegic rats: partial restoration of hind limb function. Science273, 510-513.
33. Cheng, H., Almström, S., Giménez-Llort, L., Chang, R., Ove Ögren, S., Hoffer, B. and Olson, L. (1997). Gait analysis of adult paraplegic rats after spinal cord repair. Exp. Neurol. 148, 544-557.
34. Citron, B. A., and Arnold, P. M., Sebastian, C., Qin, F., Malladi, S., Ameenuddin, S., Landis, M. E. and Festoff, B. W. (2000). Rapid upregulation of caspase-3 in rat spinal cord after injury: mRNA, protein, and cellular localization correlates with apoptotic cell death. Exp. Neurol. 166, 213-226.
35. Clark, F. M. and Proudfit, H. K. (1992). Anatomical evidence for genetic differences in the innervation of the rat spinal cord by noradrenergic locus coeruleus neurons. Brain Res. 591, 44-53.
36. Cohen, D. M., and Patel, C. B., Ahobila-Vajjula, P., Sundberg, L. M., Chacko, T., Liu, S.-J. and Narayana, P. A. (2009). Blood-spinal cord barrier permeability in experimental spinal cord injury: dynamic contrast-enhanced MRI. NMR Biomed. 22, 332-341.
37. Courtine, G., Song, B., Roy, R. R., Zhong, H., and Herrmann, J. E., Ao, Y., Qi, J., Edgerton, V. R. and Sofroniew, M. V. (2008). Recovery of supraspinal control of stepping via indirect propriospinal relay connections after spinal cord injury. Nat. Med. 14, 69-74.
38. Cregg, J. M., and DePaul, M. A., Filous, A. R., Lang, B. T., Tran, A. and Silver, J. (2014). Functional Regeneration beyond the glial scar. Exp. Neurol. 253, 197-207.
39. Crowe, M. J., and Bresnahan, J. C., Shuman, S. L., Masters, J. N. and Crowe, M. S. (1997). Apoptosis and delayed degeneration after spinal cord injury in rats and monkeys. Nat. Med. 3, 73-76.
40. DePaul, M. A., Lin, C.-Y., Silver, J. and Lee, Y.-S. (2015). Peripheral nerve transplantation combined with acidic fibroblast growth factor and chondroitinase induces regeneration and improves urinary function in complete spinal cord transected adult mice. PLoS ONE 10, e0139335.
41. Dickendesher, T. L., and Baldwin, K. T., Mironova, Y. A., Koriyama, Y., Raiker, S. J., and Askew, K. L., Wood, A., Geoffroy, C. G., Zheng, B., Liepmann, C. D. et al. (2012). NgR1 and NgR3 are receptors for chondroitin sulfate proteoglycans. Nat. Neurosci. 15, 703-712.
42. Didangelos, A., Puglia, M., Iberl, M., Sanchez-Bellot, C., Roschitzki, B. and Bradbury, E. J. (2016). High-throughput proteomics reveal alarmins as amplifiers of tissue pathology and inflammation after spinal cord injury. Sci. Rep. 6, 21607.
43. Dimar, J. R., and Glassman, S. D., Raque, G. H., Zhang, Y. P. and Shields, C. B. (1999). The influence of spinal canal narrowing and timing of decompression on neurologic recovery after spinal cord contusion in a rat model. Spine 24, 1623-1633.
44. Dolan, E. J., Tator, C. H. and Endrenyi, L. (1980). The value of decompression for acute experimental spinal cord compression injury. J. Neurosurg. 53, 749-755.
45. Donatelle, J. M. (1977). Growth of the corticospinal tract and the development of placing reactions in the postnatal rat. J. Comp. Neurol. 175, 207-231.
46. Doucette, R. (1990). Glial influences on axonal growth in the primary olfactory system. Glia 3, 433-449.
47. Doucette, R. (1995). Olfactory ensheathing cells: potential for glial cell transplantation into areas of CNS injury. Histol. Histopathol. 10, 503-507.
48. Emery, E., Aldana, P., Bunge, M. B., Puckett, W., Srinivasan, A., Keane, R. W., Bethea, J. and Levi, A. D.O. (1998). Apoptosis after traumatic human spinal cord injury. J. Neurosurg. 89, 911-920.
49. Erschbamer, M., Pernold, K. and Olson, L. (2007). Inhibiting epidermal growth factor receptor improves structural, locomotor, sensory, and bladder recovery from experimental spinal cord injury. J. Neurosci. 27, 6428-6435.
50. European Medical Agency. (2004). Glivec: EPAR - Scientific Discussion, 406, 1-61.
51. Faden, A. I. and Simon, R. P. (1988). A potential role for excitotoxins in the pathophysiology of spinal cord injury. Ann. Neurol. 23, 623-626.
52. Faden, A. I., Ellison, J. A. and Noble, L. J. (1990). Effects of competetive and non-competetive NMDA receptor antagonists in spinal cord injury. Eur. J. Pharmacol. 40, 482-490.
53. Failli, V., and Kopp, M. A., Gericke, C., Martus, P., Klingbeil, S., Brommer, B., Laginha, I., Chen, Y., and DeVivo, M. J., Dirnagl, U. et al. (2012). Functional neurological recovery after spinal cord injury is impaired in patients with infections. Brain 135, 3238-3250.
54. Faulkner, J. and Keirstead, H. S. (2005). Human embryonic stem cell-derived oligodendrocyte progenitors for the treatment of spinal cord injury. Transplant Immunol. 15, 131-142.
55. Fehlings, M. G. and Perrin, R. G. (2005). The role and timing of early decompression for cervical spinal cord injury: update with a review of recent clinical evidence. Injury 36 Suppl. 2, S13-S26.
56. Fehlings, M. G., Nakashima, H., Nagoshi, N., Chow, D. S., Grossman, R. G. and Kopjar, B. (2015). Rationale, design and critical end points for the Riluzole in Acute Spinal Cord Injury Study (RISCIS): a randomized, double-blinded, placebo-controlled parallel multi-center trial. Spinal Cord 54, 8-15.
57. Field-Fote, E. (2002). Spinal cord stimulation facilitates functional walking in a chronic, incomplete spinal cord injured subject. Spinal Cord 40, 428.
58. Figley, S. A., Khosravi, R., Legasto, J. M., Tseng, Y.-F. and Fehlings, M. G. (2014). Characterization of vascular disruption and blood-spinal cord barrier permeability following traumatic spinal cord injury. J. Neurotrauma 31, 541-552.
59. Filli, L., and Engmann, A. K., Zorner, B., Weinmann, O., Moraitis, T., Gullo, M., Kasper, H., Schneider, R. and Schwab, M. E. (2014). Bridging the gap: a reticulo-propriospinal detour bypassing an incomplete spinal cord injury. J. Neurosci. 34, 13399-13410.
60. Fleming, J. C., and Norenberg, M. D., Ramsay, D. A., Dekaban, G. A., and Marcillo, A. E., Saenz, A. D., Pasquale-Styles, M., Dietrich, W. D. and Weaver, L. C. (2006). The cellular inflammatory response in human spinal cords after injury. Brain 129, 3249-3269.
61. Fraidakis, M., Klason, T., Cheng, H., Olson, L. and Spenger, C. (1998). Highresolution MRI of intact and transected rat spinal cord. Exp. Neurol. 153, 299-312.
62. Fraidakis, M. J., Spenger, C. and Olson, L. (2004). Partial recovery after treatment of chronic paraplegia in rat. Exp. Neurol. 188, 33-42.
63. Fredriksson, L., Stevenson, T.K., Su, E. J., Ragsdale, M., Moore, S., Craciun, S., Schielke, G. P., Murphy, G. G. and Lawrence, D. A. (2015). Identification of a neurovascular signaling pathway regulating seizures in mice. Ann. Clin. Transl. Neurol. 2, 722-738.
64. Friedli, L. Rosenzweig, E. S., Barraud, Q., Schubert, M., Dominici, N., Awai, L., Nielson, J. L., Musienko, P., Nout-Lomas, Y., Zhong, H. et al. (2015). Pronounced species divergence in corticospinal tract reorganization and functional recovery after lateralized spinal cord injury favors primates. Sci. Transl. Med. 7, 302ra134.
65. Geremia, N. M., Bao, F., Rosenzweig, T. E., Hryciw, T., Weaver, L., Dekaban, G. A. and Brown, A. (2012). CD11d antibody treatment improves recovery in spinal cord-injured mice. J. Neurotrauma 29, 539-550.
66. Gomes-Osman, J., Cortes, M., Guest, J. and Pascual-Leone, A. (2016). A systematic review of experimental strategies aimed at improving motor function after acute and chronic spinal cord injury. J. Neurotrauma 33, 425-438.
67. Göritz, C., and Dias, D. O., Tomilin, N., Barbacid, M., Shupliakov, O. and Frisen, J. (2011). A pericyte origin of spinal cord scar tissue. Science 333, 238-242.
68. Graziadei, P. P. C. and Graziadei, G. A. M. (1979). Neurogenesis and neuron regeneration in the olfactory system of mammals. I. Morphological aspects of differentiation and structural organization of the olfactory sensory neurons. J. Neurocytol. 8, 1-18.
69. Griffiths, I. R. (1976). Spinal cord blood flow after acute experimental cord injury in dogs. J. Neurol. Sci. 27, 247-259.
70. Gruner, J. A. (1992). A monitored contusion model of spinal cord injury in the rat. J. Neurotrauma 9, 123-128.
71. Guerrero, A. R., Uchida, K., Nakajima, H., Watanabe, S., Nakamura, M., Johnson, W. E. B. and Baba, H. (2012). Blockade of interleukin-6 signaling inhibits the classic pathway and promotes an alternative pathway of macrophage activation after spinal cord injury in mice. J. Neuroinflamm. 9, 40.
72. Guest, J. and Dietrich, W. D. (2015). Commentary regarding the recent publication by Tabakow et al., "Functional regeneration of supraspinal connections in a patient with transected spinal cord following transplantation of bulbar olfactory ensheathing cells with peripheral nerve bridging". J. Neurotrauma 32, 1176-1178.
73. Guest, J. D., Rao, A., Olson, L., Bunge, M. B. and Bunge, R. P. (1997). The ability of human Schwann cell grafts to promote regeneration in the transected nude rat spinal cord. Exp. Neurol. 148, 502-522.
74. Guth, L., Zhang, Z. and Steward, O. (1999). The unique histopathological responses of the injured spinal cord: implications for neuroprotective therapy. Ann. N. Y. Acad. Sci. 890, 366-384.
75. Hahn, C.-G., Han, L.-Y., and Rawson, N. E., Mirza, N., Borgmann-Winter, K., Lenox, R. H. and Arnold, S. E. (2005). In vivo and in vitro neurogenesis in human olfactory epithelium. J. Comp. Neurol. 483, 154-163.
76. Hamers, F. P. T., and Lankhorst, A. J., Van Laar, T. J., Veldhuis, W. B. and Gispen, W. H. (2001). Automated quantitative gait analysis during overground locomotion in the rat: its application to spinal cord contusion and transection injuries. J. Neurotrauma 18, 187-201.
77. Harding, J., Graziadei, P. P. C., Graziadei, G. A. M. and Margolis, F. L. (1977). Denervation in the primary olfactory pathway of mice. IV. Biochemical and morphological evidence for neuronal replacement following nerve section. Brain Res. 132, 11-28.
78. Hauben, E., Butovsky, O., Nevo, U., Yoles, E., Moalem, G., Agranov, E., Mor, F., Leibowitz-Amit, R., Pevsner, E., Akselrod, S. et al. (2000a). Passive or active immunization with myelin basic protein promotes recovery from spinal cord contusion. J. Neurosci. 20, 6421-6430.
79. Hauben, E., Nevo, U., Yoles, E., Moalem, G., Agranov, E., Mor, F., Akselrod, S., Neeman, M., Cohen, I. R. and Schwartz, M. (2000b). Autoimmune T cells as potential neuroprotective therapy for spinal cord injury. Lancet 355, 286-287.
80. Hawthorne, A. L. and Popovich, P. G. (2011). Emerging concepts in myeloid cell biology after spinal cord injury. Neurotherapeutics 8, 252-261.
81. Hayashi, Y., Nakamae, H., Katayama, T., Nakane, T., Koh, H., Nakamae, M., Hirose, A., Hagihara, K., Terada, Y., Nakao, Y. et al. (2012). Different immunoprofiles in patients with chronic myeloid leukemia treated with imatinib, nilotinib or dasatinib. Leukemia Lymphoma 53, 1084-1089.
82. Hayes, K. C., Hull, T. C. L., Delaney, G. A., and Potter, P. J., Sequeira, K. A. J., Campbell, K. and Popovich, P. G. (2002). Elevated serum titers of proinflammatory cytokines and CNS autoantibodies in patients with chronic spinal cord injury. J. Neurotrauma 19, 753-761.
83. Heppner, F. L., Ransohoff, R. M. and Becher, B. (2015). Immune attack: the role of inflammation in Alzheimer disease. Nat. Rev. Neurosci. 16, 358-372.
84. Hermanns, S., Reiprich, P. and Müller, H. W. (2001). A reliable method to reduce collagen scar formation in the lesioned rat spinal cord. J. Neurosci. Methods 110, 141-146.
85. Hofstetter, C. P., Holmström, N. A. V., Lilja, J. A., Schweinhardt, P., Hao, J., Spenger, C., Wiesenfeld-Hallin, Z., Kurpad, S. N., Frisén, J. and Olson, L. (2005). Allodynia limits the usefulness of intraspinal neural stem cell grafts; directed differentiation improves outcome. Nat. Neurosci. 8, 346-353.
86. Huang, D. W., McKerracher, L., Braun, P. E. and David, S. (1999). A therapeutic vaccine approach to stimulate axon regeneration in the adult mammalian spinal cord. Neuron 24, 639-647.
87. Inman, D. M. and Steward, O. (2003). Ascending sensory, but not other long-tract axons, regenerate into the connective tissue matrix that forms at the site of a spinal cord injury in mice. J. Comp. Neurol. 462, 431-449.
88. Iwanami, A., Kaneko, S., Nakamura, M., Kanemura, Y., Mori, H., Kobayashi, S., Yamasaki, M., Momoshima, S., Ishii, H., Ando, K. et al. (2005). Transplantation of human neural stem cells for spinal cord injury in primates. J. Neurotrauma 80, 182-190.
89. Jani, H. R. and Raisman, G. (2004). Ensheathing cell cultures from the olfactory bulb and mucosa. Glia 47, 130-137.
90. Jones, T. B., (2004). Passive or active immunization with myelin basic protein impairs neurological function and exacerbates neuropathology after spinal cord injury in rats. J. Neurosci. 24, 3752-3761.
91. Jones, C.F., Cripton, P. A. and Kwon, B. K. (2012). Gross morphological changes of the spinal cord immediately after surgical decompression in a large animal model of traumatic spinal cord injury. Spine 37, E890-E899.
92. Josephson, A., Greitz, D., Klason, T., Olson, L. and Spenger, C. (2001). A spinal thecal sac constriction model supports the theory that induced pressure gradients in the cord cause edema and cyst formation. Neurosurgery 48, 636-645. discussion 645-646
93. Jungner, M., Siemund, R., Venturoli, D., Reinstrup, P., Schalén, W. and Bentzer, P. (2015). Blood-brain barrier permeability following traumatic brain injury. Minerva Anestesiol. 82, 525-533.
94. Kadoya, K., Lu, P., Nguyen, K., Lee-Kubli, C., Kumamaru, H., Yao, L., Knackert, J., Poplawski, G., and Dulin, J. N., Strobl, H. et al. (2016). Spinal cord reconstitution with homologous neural grafts enables robust corticospinal regeneration. Nat. Med. 22, 479-487.
95. Karlsson, T. E., Koczy, J., Brené, S., Olson, L. and Josephson, A. (2013). Differential conserted activity induced regulation of Nogo receptors (1-3), LOTUS and Nogo mRNA in mouse brain. PLoS ONE 8, e60892.
96. Kigerl, K. A., and Gensel, J. C., Ankeny, D. P., Alexander, J. K., Donnelly, D. J. and Popovich, P. G. (2009). Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord. J. Neurosci. 29, 13435-13444.
97. Kjell, J. and Olson, L. (2015). Repositioning imatinib for spinal cord injury. Neural Regener. Res. 10, 1591-1593.
98. Kjell, J., Sandor, K., Josephson, A., Svensson, C. I. and Abrams, M. B. (2013). Rat substrains differ in the magnitude of spontaneous locomotor recovery and in the development of mechanical hypersensitivity after experimental spinal cord injury. J. Neurotrauma 30, 1805-1811.
99. Kjell, J., Finn, A., Hao, J., Wellfelt, K., Josephson, A., Svensson, C. I., Wiesenfeld-Hallin, Z., Eriksson, U., Abrams, M. and Olson, L. (2015). Delayed imatinib treatment for acute spinal cord injury: functional recovery and serum biomarkers. J. Neurotrauma 32, 1645-1657.
100. Kjell, J., Olson, L. and Abrams, M. B. (2016). Improved recovery from spinal cord injury in rats with chronic parvovirus serotype-1a infection. Spinal Cord 54, 517-520.
101. Kwon, B. K., Stammers, A. M. T., Belanger, L. M., Bernardo, A., Chan, D., Bishop, C. M., and Slobogean, G. P., Zhang, H., Umedaly, H., Giffin, M. et al. (2010). Cerebrospinal fluid inflammatory cytokines and biomarkers of injury severity in acute human spinal cord injury. J. Neurotrauma 27, 669-682.
102. Kwon, B. K., Streijger, F., Hill, C. E., and Anderson, A. J., Bacon, M., Beattie, M. S., Blesch, A., and Bradbury, E. J., Brown, A., Bresnahan, J. C. et al. (2015). Large animal and primate models of spinal cord injury for the testing of novel therapies. Exp. Neurol. 269, 154-168.
103. Lankhorst, A. J., Verzijl, M. R. and Hamers, F. P. T. (1999). Experimental spinal cord contusion injury: comparison of different outcome parameters. Neurosci. Res. Commun. 24, 135-148.
104. Lee, Y.-S., Zdunowski, S., and Edgerton, V. R., Roy, R. R., Zhong, H., Hsiao, I. and Lin, V. W. (2010). Improvement of gait patterns in step-trained, complete spinal cord-transected rats treated with a peripheral nerve graft and acidic fibroblast growth factor. Exp. Neurol. 224, 429-437.
105. Lee, Y.-S., Lin, C.-Y., Jiang, H.-H., DePaul, M., Lin, V. W. and Silver, J. (2013). Nerve regeneration restores supraspinal control of bladder function after complete spinal cord injury. J. Neurosci. 33, 10591-10606.
106. Li, Y., Field, P. M. and Raisman, G. (1997). Repair of adult rat corticospinal tract by transplants of olfactory ensheathing cells. Science 277, 2000-2002.
107. Lilja, J., Endo, T., Hofstetter, C., Westman, E., Young, J., Olson, L. and Spenger, C. (2006). Blood oxygenation level-dependent visualization of synaptic relay stations of sensory pathways along the neuroaxis in response to graded sensory stimulation of a limb. J. Neurosci. 26, 6330-6336.
108. Liu, X. Z., and Xu, X. M., Hu, R., Du, C., Zhang, S. X., and McDonald, J. W., Dong, H. X., Wu, Y. J., and Fan, G. S., Jacquin, M. F. et al. (1997). Neuronal and glial apoptosis after traumatic spinal cord injury. J. Neurosci. 17, 5395-5406.
109. Lou, J., and Lenke, L. G., Ludwig, F. J. and O'brien, M. F. (1998). Apoptosis as a mechanism of neuronal cell death following acute experimental spinal cord injury. Spinal Cord 36, 683-690.
110. Loy, D. N., and Crawford, C. H., Darnall, J. B., Burke, D. A., Onifer, S. M. and Whittemore, S. R. (2002). Temporal progression of angiogenesis and basal lamina deposition after contusive spinal cord injury in the adult rat. J. Comp. Neurol. 445, 308-324.
111. Lu, P., and Jones, L. L., Snyder, E. Y. and Tuszynski, M. H. (2003). Neural stem cells constitutively secrete neurotrophic factors and promote extensive host axonal growth after spinal cord injury. Exp. Neurol. 181, 115-129.
112. Lu, P., Wang, Y., Graham, L., McHale, K., Gao, M., Wu, D., Brock, J., Blesch, A., Rosenzweig, E. S., Havton, L. A. et al. (2012). Long-distance growth and connectivity of neural stem cells after severe spinal cord injury. Cell 150, 1264-1273.
113. Ma, M., and Basso, D. M., Walters, P., Stokes, B. T. and Jakeman, L. B. (2001). Behavioral and histological outcomes following graded spinal cord contusion injury in the C57Bl/6 mouse. Exp. Neurol. 169, 239-254.
114. Ma, Q., Huang, B., Khatibi, N., Rolland, W., Suzuki, H., Zhang, J. H. and Tang, J. (2011). PDGFR-α inhibition preserves blood-brain barrier after intracerebral hemorrhage. Ann. Neurol. 70, 920-931.
115. McBride, R. L., and Feringa, E. R., Garver, M. K. and Williams, J. K. (1990). Retrograde transport of fluoro-gold in corticospinal and rubrospinal neurons 10 and 20 weeks after T-9 spinal cord transection. Exp. Neurol. 108, 83-85.
116. Mckeon, R. J., and Schreiber, R. C., Rudge, J. S. and Silver, J. (1991). 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. 11, 3398-3411.
117. Merali, Z., Leung, J., Mikulis, D., Silver, F. and Kassner, A. (2015). Longitudinal assessment of imatinib's effect on the blood-brain barrier after ischemia/reperfusion injury with permeability MRI. Transl. Stroke Res. 6, 39-49.
118. Metz, G. A. S., Curt, A., Van De MEENT, H., Klusman, I., Schwab, M. E. and Dietz, V. (2000). Validation of the weight-drop contusion model in rats: a comparative study of human spinal cord injury. J. Neurotrauma 17, 1-17.
119. Mills, C. D., and Hains, B. C., Johnson, K. M. and Hulsebosch, C. E. (2001). Strain and model differences in behavioral outcomes after spinal cord injury in rat. J. Neurotrauma 18, 743-756.
120. Miron, V. E., Boyd, A., Zhao, J.-W., and Yuen, T. J., Ruckh, J. M., Shadrach, J.L., Van Wijngaarden, P, Wagers, A. J., Williams, A., Franklin, R. J. M. et al. (2013). M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination. Nat. Neurosci. 16, 1211-1218.
121. Modi, H. N., and Suh, S. W., Hong, J. Y. and Yang, J. H. (2011). The effects of spinal cord injury induced by shortening on motor evoked potentials and spinal cord blood flow: an experimental study in Swine. J. Bone Joint Surg. Am. 93, 1781-1789.
122. Monti Graziadei, G. A., Karlan, M. S., Bernstein, J. J. and Graziadei, P. P. C. (1980). Reinnervation of the olfactory bulb after section of the olfactory nerve in monkey (Saimiri sciureus). Brain Res. 189, 343-354.
123. Nagoshi, N., Nakashima, H. and Fehlings, M. G. (2015). Riluzole as a neuroprotective drug for spinal cord injury: from bench to bedside. Molecules 20, 7775-7789.
124. Nakajima, H., Uchida, K., Guerrero, A. R., Watanabe, S., Sugita, D., Takeura, N., Yoshida, A., Long, G., Wright, K. T., Johnson, W. E. B. et al. (2012). Transplantation of mesenchymal stem cells promotes an alternative pathway of macrophage activation and functional recovery after spinal cord injury. J. Neurotrauma 29, 1614-1625.
125. Nandoe Tewarie, R. D. S. Yu, J, Seidel, J, Rahiem, S. T., Hurtado, A., Tsui, B. M., Grotenhuis, J. A., Pomper, M. G. and Oudega, M. (2010). Positron emission tomography for serial imaging of the contused adult rat spinal cord. Mol. Imaging 9, 108-116.
126. Nathan, P. W. (1994). Effects on movement of surgical incisions into the human spinal cord. Brain 117, 337-346.
127. National Spinal Cord Injury Statistical Center. (2016). Spinal Cord Injury (SCI) Facts and Figures at a Glance. J. Spinal Cord Med. 39, 370-371.
128. Nielsen, J. B. (2003). How we walk: central control of muscle activity during human walking. Neuroscientist 9, 195-204.
129. Norenberg, M. D., Smith, J. and Marcillo, A. (2004). The pathology of human spinal cord injury: defining the problems. J. Neurotrauma 21, 429-440.
130. Nygren, L. G., Fuxe, K., Jonsson, G. and Olson, L. (1974). Functional regeneration of 5-hydroxytryptamine nerve terminals in the rat spinal cord following 5,6-dihydroxytryptamine induced degeneration. Brain Res. 78, 377-394.
131. Olson, L. (1997). Regeneration in the adult central nervous system: experimental repair strategies. Nat. Med. 3, 1329-1335.
132. Olson, L. (2013). Combinatory treatments needed for spinal cord injury. Exp. Neurol. 248, 309-315.
133. Onifer, S. M., Rabchevsky, A.G. and Scheff, S.W. (2007). Ratmodels of traumatic spinal cord injury to assess motor recovery. ILAR J. 48, 385-395.
134. Petersen, T. H., Willerslev-Olsen, M., Conway, B. A. and Nielsen, J. B. (2012). The motor cortex drives the muscles during walking inhuman subjects. J. Physiol. 590, 2443-2452.
135. Phang, I., Werndle, M. C. and Saadoun, S., Varsos, G., Czosnyka, M., Zoumprouli, A. and Papadopoulos, M. C. (2015). Expansion duroplasty improves intraspinal pressure, spinal cord perfusion pressure, and vascular pressure reactivity index in patients with traumatic spinal cord injury: Injured Spinal Cord Pressure Evaluation Study. J. Neurotrauma 32, 865-874.
136. Popovich, P. G., and Horner, P. J., Mullin, B. B. and Stokes, B. T. (1996). A quantitative spatial analysis of the blood-spinal cord barrier. I. Permeability changes after experimental spinal contusion injury. Exp. Neurol. 142, 258-275.
137. Popovich, P. G., Wei, P. and Stokes, B. T. (1997). Cellular inflammatory response after spinal cord injury in Sprague-Dawley and Lewis rats. J. Comp. Neurol. 377, 443-464.
138. Raineteau, O. and Schwab, M. E. (2001). Plasticity of motor systems after incomplete spinal cord injury. Nat. Rev. Neurosci. 2, 263-273.
139. Raisman, G. and Li, Y. (2007). Repair of neural pathways by olfactory ensheathing cells. Nat. Rev. Neurosci. 8, 312-319.
140. Ramón-Cueto, A. and Valverde, F. (1995). Olfactory bulb ensheathing glia: a unique cell type with axonal growth-promoting properties. Glia 14, 163-173.
141. Rapalino, O., Lazarov-Spiegler, O., Agranov, E., and Velan, G. J., Yoles, E., Fraidakis, M., Soloman, A., Gepstein, R., Katz, A., Belkin, M. et al. (1998). Implantation of stimulated homologous macrophages results in partial recovery of paraplegic rats. Nat. Med. 4, 814-821.
142. Reier, P. J., and Lane, M. A., Hall, E. D., Teng, Y. D. and Howland, D. R. (2012). Translational spinal cord injury research: preclinical guidelines and challenges. Handb. Clin. Neurol. 109, 411-433.
143. Richardson, P.M., Mcguinness, U. M. and Aguayo, A. J. (1980). Axons from CNS neurones regenerate into PNS grafts. Nature 284, 264-265.
144. Rivlin, A. S. and Tator, C. H. (1978). Effect of duration of acute spinal cord compression in a new acute cord injury model in the rat. Surg. Neurol. 10, 38-43.
145. Rosenzweig, E. S. and McDonald, J. W. (2004). Rodent models for treatment of spinal cord injury: research trends and progress toward useful repair. Curr. Opin. Neurol. 17, 121-131.
146. Rosenzweig, E. S., Courtine, G., Jindrich, D. L., and Brock, J. H., Ferguson, A. R., Strand, S. C., and Nout, Y. S., Roy, R. R., Miller, D. M., Beattie, M. S. et al. (2010). Extensive spontaneous plasticity of corticospinal projections after primate spinal cord injury. Nat. Neurosci. 13, 1505-1510.
147. Scheff, S. W., Saucier, D. A. and Cain, M. E. (2002). A statistical method for analyzing rating scale data: the BBB locomotor score. J. Neurotrauma 19, 1251-1260.
148. Scheff, S. W., and Rabchevsky, A. G., Fugaccia, I., Main, J. A. and Lumpp, J. E. (2003). Experimental modeling of spinal cord injury: characterization of a force-defined injury device. J. Neurotrauma 20, 179-193.
149. Schucht, P., Raineteau, O., Schwab, M. E. and Fouad, K. (2002). Anatomical correlates of locomotor recovery following dorsal and ventral lesions of the rat spinal cord. Exp. Neurol. 176, 143-153.
150. Schumacher, P. A., Siman, R. G. and Fehlings, M. G. (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, 1646-1655.
151. Schwartz, G. and Fehlings, M. G. (2001). Evaluation of the neuroprotective effects of sodium channel blockers after spinal cord injury: improved behavioral and neuroanatomical recovery with riluzole. J. Neurosurg. 94 2 Suppl., 245-256.
152. Schwab, M. (2010). Functions of Nogo proteins and their receptors in the nervous system. Nat. Rev. Neurosci. 11, 799-811.
153. Schwob, J. E. (2002). Neural regeneration and the peripheral olfactory system. Anat. Rec. 269, 33-49.
154. Silver, J. and Miller, J. H. (2004). Regeneration beyond the glial scar. Nat. Rev. Neurosci. 5, 146-156.
155. Silver, J., Schwab, M. E. and Popovich, P. G. (2014). Central nervous system regenerative failure: role of oligodendrocytes, astrocytes, and microglia. Cold Spring Harb. Perspect. Biol. 7, a020602.
156. Soderblom, C., Luo, X., Blumenthal, E., Bray, E., Lyapichev, K., Ramos, J., Krishnan, V., Lai-Hsu, C., Park, K. K., Tsoulfas, P. et al. (2013). Perivascular fibroblasts form the fibrotic scar after contusive spinal cord injury. J. Neurosci. 33, 13882-13887.
157. Sroga, J. M., and Jones, T. B., Kigerl, K. A., McGaughy, V. M. and Popovich, P. G. (2003). Rats and mice exhibit distinct inflammatory reactions after spinal cord injury. J. Comp. Neurol. 462, 223-240.
158. Stichel, C. C., Niermann, H., D'urso, D., Lausberg, F., Hermanns, S. and Muller, H. W. (1999). Basal membrane-depleted scar in lesioned CNS: characteristics and relationships with regenerating axons. Neuroscience 93, 321-333.
159. Stirling, D. P., Liu, S., Kubes, P. and Yong, V. W. (2009). Depletion of Ly6G/Gr-1 leukocytes after spinal cord injury in mice alters wound healing and worsens neurological outcome. J. Neurosci. 29, 753-764.
160. Su, E. J., Fredriksson, L., Geyer, M., Folestad, E., Cale, J., Andrae, J., Gao, Y., Pietras, K., Mann, K., Yepes, M. et al. (2008). Activation of PDGF-CC by tissue plasminogen activator impairs blood-brain barrier integrity during ischemic stroke. Nat. Med. 14, 731-737.
161. Su, E. J., Fredriksson, L., Schielke, G. P., Eriksson, U. and Lawrence, D. A. (2009). Tissue plasminogen activator-mediated PDGF signaling and neurovascular coupling in stroke. J. Thromb. Haemostasis 7 Suppl. 1, 155-158.
162. Su, E. J., Fredriksson, L., Kanzawa, M., Moore, S., Folestad, E., Stevenson, T. K., Nilsson, I., Sashindranath, M., Schielke, G. P., Warnock, M. et al. (2015). Imatinib treatment reduces brain injury in a murine model of traumatic brain injury. Front. Cell. Neurosci. 9, 385.
163. Tabakow, P., Jarmundowicz, W., Czapiga, B., Fortuna, W., Miedzybrodzki, R., Czyz, M., Huber, J., Szarek, D., Okurowski, S., Szewczyk, P. et al. (2013). Transplantation of autologous olfactory ensheathing cells in complete human spinal cord injury. Cell Transplant. 22, 1591-1612.
164. Tabakow, P., Raisman, G., Fortuna, W., Czyz, M., Huber, J., Li, D., Szewczyk, P., Okurowski, S., Miedzybrodzki, R., Czapiga, B. et al. (2014). Functional regeneration of supraspinal connections in a patient with transected spinal cord following transplantation of bulbar olfactory ensheathing cells with peripheral nerve bridging. Cell Transplant. 23, 1631-1655.
165. Taoka, Y., Okajima, K., Uchiba, M., Murakami, K., Kushimoto, S., Johno, M., Naruo, M., Okabe, H. and Takatsuki, K. (1997). Role of neutrophils in spinal cord injury in the rat. Neuroscience 79, 1177-1182.
166. Tator, C. H. (1995). Update on the pathophysiology and pathology of acute spinal cord injury. Brain Pathol. 5, 407-413.
167. Tello, F. (1911). La influencia del neurotropismo en la regeneracion de los centros nerviosos. Trab Lab Invest Biol Univ Madrid 9, 123-159.
168. Teng, Y. D. and Wrathall, J. R. (1997). Local blockade of sodium channels by tetrodotoxin ameliorates tissue loss and long-term functional deficits resulting from experimental spinal cord injury. J. Neurosci. 17, 4359-4366.
169. Tuszynski, M. H., Wang, Y., Graham, L., McHale, K., Gao, M., Wu, D., Brock, J., Blesch, A., Rosenzweig, E. S., Havton, L. A. et al. (2014). Neural stem cells in models of spinal cord injury. Exp. Neurol. 261, 494-500.
170. Van Den Brand, R., Heutschi, J., Barraud, Q., Digiovanna, J., Bartholdi, K., Huerlimann, M., Friedli, L., Vollenweider, I., and Moraud, E. M., Duis, S. et al. (2012). Restoring voluntary control of locomotion after paralyzing spinal cord injury. Science336, 1182-1185.
171. Van Middendorp, J. J., Sanchez, G. M. and Burridge, A. L. (2010). The Edwin Smith papyrus: a clinical reappraisal of the oldest known document on spinal injuries. Eur. Spine J. 19, 1815-1823.
172. Vanický, I., Urdzíková, L., Saganová, K., Čízková, D. and Gálik, J. (2001). A simple and reproducible model of spinal cord injury induced by epidural balloon inflation in the rat. J. Neurotrauma 18, 1399-1407.
173. Watson, C., Paxinos, G. and Kayalioglu, G. (2009). In The Spinal Cord: A Christopher and Dana Reeve Foundation Text and Atlas. Elsevier.
174. Watzlawick, R., Rind, J., Sena, E. S., Brommer, B., Zhang, T., Kopp, M. A., Dirnagl, U., and Macleod, M. R., Howells, D. W. and Schwab, J. M. (2016). Olfactory ensheathing cell transplantation in experimental spinal cord injury: effect size and reporting bias of 62 experimental treatments: a systematic review and meta-analysis. PLoS Biol. 14, e1002468.
175. Wenger, N., and Moraud, E. M., Raspopovic, S., Bonizzato, M., DiGiovanna, J., Musienko, P., Morari, M., Micera, S. and Courtine, G. (2014). Closed-loop neuromodulation of spinal sensorimotor circuits controls refined locomotion after complete spinal cord injury. Sci. Transl. Med. 6, 255ra133.
176. Wenger, N., and Moraud, E. M., Gandar, J., Musienko, P., Capogrosso, M., Baud, L., Le Goff, C. G., Barraud, Q., Pavlova, N., Dominici, N. et al. (2016). Spatiotemporal neuromodulation therapies engaging muscle synergies improve motor control after spinal cord injury. Nat. Med. 22, 138-145.
177. Williams, R. R., Henao, M., Pearse, D. D. and Bunge, M. B. (2015). Permissive Schwann cell graft/spinal cord interfaces for axon regeneration. Cell Transplant. 24, 115-131.
178. Wu, X., Liu, J., Tanadini, L. G., and Lammertse, D. P., Blight, A. R., Kramer, J. L. K., Scivoletto, G., Jones, L., Kirshblum, S., Abel, R. et al. (2015). Challenges for defining minimal clinically important difference (MCID) after spinal cord injury. Spinal Cord 53, 84-91.
179. Xu, N., Åkesson, E., Holmberg, L. and Sundström, E. (2015). A sensitive and reliable test instrument to assess swimming in rats with spinal cord injury. Behav. Brain Res. 291, 172-183.
180. Zhang, Z., Krebs, C. J. and Guth, L. (1997). Experimental analysis of progressive necrosis after spinal cord trauma in the rat: etiological role of the inflammatory response. Exp. Neurol. 143, 141-152.
181. Zörner, B., Filli, L., Starkey, M. L., Gonzenbach, R., Kasper, H., Röthlisberger, M., Bolliger, M. and Schwab, M. E. (2010). Profiling locomotor recovery: comprehensive quantification of impairments after CNS damage in rodents. Nat. Methods 7, 701-708.