title: Novel combination strategies to repair the injured mammalian spinal cord.
abstract: Due to the varied and numerous changes in spinal cord tissue following injury, successful treatment for repair may involve strategies combining neuroprotection (pharmacological prevention of some of the damaging intracellular cascades that lead to secondary tissue loss), axonal regeneration promotion (cell transplantation, genetic engineering to increase growth factors, neutralization of inhibitory factors, reduction in scar formation), and rehabilitation. Our goal has been to find effective combination strategies to improve outcome after injury to the adult rat thoracic spinal cord. Combination interventions tested have been implantation of Schwann cells (SCs) plus neuroprotective agents and growth factors administered in various ways, olfactory ensheathing cell (OEC) implantation, chondroitinase addition, or elevation of cyclic AMP. The most efficacious strategy in our hands for the acute complete transection/SC bridge model, including improvement in locomotion [Basso, Beattie, Bresnahan Scale (BBB)], is the combination of SCs, OECs, and chondroitinase administration (BBB 2.1 vs 6.6, 3 times more myelinated axons in the SC bridge, increased serotonergic axons in the bridge and beyond, and significant correlation between the number of bridge myelinated axons and functional improvement). We found the most successful combination strategy for a subacute spinal cord contusion injury (12.5-mm, 10-g weight, MASCIS impactor) to be SCs and elevation of cyclic AMP (BBB 10.4 vs 15, significant increases in white matter sparing, in myelinated axons in the implant, and in responding reticular formation and red and raphe nuclei, and a significant correlation between the number of serotonergic fibers and improvement in locomotion). Thus, in two injury paradigms, these combination strategies as well as others studied in our laboratory have been found to be more effective than SCs alone and suggest ways in which clinical application may be developed.
authors.affiliation: The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, Florida 33101, USA. MBunge@miami.edu
authors.forename: Mary Bartlett
authors.initials: MB
authors.lastname: Bunge
mesh_terms: D000818:Animals; D002810:Chondroitinases and Chondroitin Lyases / Q000008:administration & dosage*; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D009832:Olfactory Nerve / Q000166:cytology*; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology; D012583:Schwann Cells / Q000637:transplantation*; D013119:Spinal Cord Injuries / Q000378:metabolism / Q000628:therapy*
chemical_list: D000242:Cyclic AMP; D002810:Chondroitinases and Chondroitin Lyases
references.citation: J Neurosci. 1998 May 15;18(10):3803-15
references.pmid: 9570810
references.citation: Expert Opin Biol Ther. 2006 Jul;6(7):639-52
references.pmid: 16805705
references.citation: J Comp Neurol. 1995 Jan 2;351(1):145-60
references.pmid: 7896937
references.citation: J Neurotrauma. 2007 Oct;24(10):1667-73
references.pmid: 17970629
references.citation: J Neurosci. 2001 Jul 1;21(13):4731-9
references.pmid: 11425900
references.citation: J Neurosci. 2002 Aug 1;22(15):6670-81
references.pmid: 12151546
references.citation: Neuroscience. 2003;118(1):271-81
references.pmid: 12676157
references.citation: EMBO J. 1994 Dec 15;13(24):5896-909
references.pmid: 7529173
references.citation: Anat Rec B New Anat. 2003 Mar;271(1):77-85
references.pmid: 12619089
references.citation: Eur J Neurosci. 1998 Feb;10(2):607-21
references.pmid: 9749723
references.citation: Nat Clin Pract Neurol. 2007 Mar;3(3):152-61
references.pmid: 17342191
references.citation: Exp Neurol. 1995 Aug;134(2):261-72
references.pmid: 7556546
references.citation: Nature. 1980 Mar 20;284(5753):264-5
references.pmid: 7360259
references.citation: Mol Cell Neurosci. 2001 Mar;17(3):471-87
references.pmid: 11273643
references.citation: Exp Neurol. 2007 Oct;207(2):203-17
references.pmid: 17719577
references.citation: Glia. 2006 Feb;53(3):338-43
references.pmid: 16267833
references.citation: J Chem Neuroanat. 1993 Jul-Aug;6(4):191-9
references.pmid: 8397920
references.citation: J Neurocytol. 1984 Feb;13(1):165-82
references.pmid: 6707710
references.citation: J Neurol Phys Ther. 2005 Jun;29(2):55-69
references.pmid: 16386163
references.citation: J Neurotrauma. 2006 Mar-Apr;23(3-4):453-67
references.pmid: 16629629
references.citation: J Neurocytol. 1997 Jan;26(1):1-16
references.pmid: 9154524
references.citation: J Neurosci. 2004 Jul 14;24(28):6402-9
references.pmid: 15254096
references.citation: NeuroRx. 2004 Jan;1(1):80-100
references.pmid: 15717009
references.citation: Neuroscientist. 2001 Aug;7(4):325-39
references.pmid: 11488398
references.citation: J Neurosci. 2005 Feb 2;25(5):1169-78
references.pmid: 15689553
references.citation: Cell Transplant. 1998 Mar-Apr;7(2):187-96
references.pmid: 9588600
references.citation: Keio J Med. 2005 Mar;54(1):8-14
references.pmid: 15832075
references.citation: Science. 1981 Nov 20;214(4523):931-3
references.pmid: 6171034
references.citation: Nat Rev Neurosci. 2007 Apr;8(4):312-9
references.pmid: 17342173
references.citation: Nat Rev Neurosci. 2006 Aug;7(8):628-43
references.pmid: 16858391
references.citation: Exp Neurol. 1996 Apr;138(2):261-76
references.pmid: 8620925
references.citation: J Neurotrauma. 2006 Mar-Apr;23(3-4):468-78
references.pmid: 16629630
references.citation: Nat Med. 2004 Jun;10(6):610-6
references.pmid: 15156204
references.citation: Glia. 2007 Jul;55(9):976-1000
references.pmid: 17526000
references.citation: NeuroRx. 2004 Oct;1(4):424-51
references.pmid: 15717046
references.citation: J Comp Neurol. 1999 Nov 1;413(4):495-506
references.pmid: 10495438
references.citation: Acta Physiol (Oxf). 2007 Feb;189(2):181-9
references.pmid: 17250568