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Review Setting the Stage for Functional Repair of Spinal Cord Injuries

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Review Setting the Stage for Functional Repair of Spinal Cord Injuries Spinal Cord (2005) 43, 134–161 & 2005 International Spinal Cord Society All rights reserved 1362-4393/05 $30.00 www.nature.com/sc Review Setting the stage for functional repair of spinal cord injuries: a cast of thousands LM Ramer1, MS Ramer1 and JD Steeves*,1 1ICORD (International Collaboration on Repair Discoveries), The University of British Columbia, Vancouver, BC, Canada Here we review mechanisms and molecules that necessitate protection and oppose axonal growth in the injured spinal cord, representing not only a cast ofvillains but also a company of therapeutic targets, many ofwhich have yet to be fullyexploited. We next discuss recent progress in the fields ofbridging, overcoming conduction block and rehabilitation after spinal cord injury (SCI), where several treatments in each category have entered the spotlight, and some are being tested clinically. Finally, studies that combine treatments targeting different aspects ofSCI are reviewed. Although experiments applying some treatments in combination have been completed, auditions for each part in the much-sought combination therapy are ongoing, and performers must demonstrate robust anatomical regeneration and/or significant return of function in animal models before being considered for a lead role. Spinal Cord (2005) 43, 134–161. doi:10.1038/sj.sc.3101715; Published online 25 January 2005 Keywords: spinal cord injury; neuroprotection; transplantation; rehabilitation; plasticity; regeneration Introduction For clinician and scientist alike, the injured spinal cord them. It is widely acknowledged that a combination of is a formidable scene: a large cast of endogenous cells treatments will be required to address the complex issues and molecules act in concert to prevent or restrict ofSCI; 1 however, designing such a treatment strategy is functional connectivity. The players and their roles in incredibly daunting. The first step is to identify the most limiting spinal cord repair continue to be elucidated, and powerful and/or versatile performers to fill the roles of each discovery unveils the character ofa molecular protection, stimulating growth, bridging, conduction antagonist that hinders return of function after spinal and rehabilitation: each treatment must audition in cord injury (SCI). As the villains reveal themselves, our isolation before it can take the stage as part of a repertoire ofpossible targets forintervention grows, and combination therapy. The second step is equally potential treatments fall into one or more of five ambitious: once the protagonists ofSCI are identified, categories: (1) protection, to prevent death ofneural they must appear in the appropriate spatial andtemporal cells undamaged by the initial injury; (2) stimulating combination. Like a performance, the development of a axonal growth, either by enhancing the intrinsic regen- reliable therapy for SCI must be directed with intimate erative capacity ofspinal and supraspinal neurons or by knowledge ofeach character, leading to the perfect blocking or removing endogenous inhibitors to repair; balance among the players. (3) bridging, to provide a permissive substrate for elongating axons and to replace lost tissue; (4) enhancing Neuroprotection in the setting of SCI axonal transmission, to alleviate conduction block in spared or regenerated axons and (5) rehabilitation,to Although traumatic SCI is often the result of a single enhance functional plasticity within surviving circuits mechanical insult, the functional outcome is determined and consolidate anatomical repair. by a cascade ofbehind-the-scenes events described As the cast ofvillains in SCI is vast and collaborative, collectively as ‘secondary injury’. Displacement or so too must be the chorus ofheroes that rise to meet penetration ofthe spinal cord both inflicts direct tissue damage (ie primary injury) and initiates destructive processes that expand the injury site. This phenomenon *Correspondence: JD Steeves, ICORD (International Collaboration on Repair Discoveries), The University ofBritish Columbia, Rm. 2469 of secondary injury, which extends for days after Biosciences Bldg., 6270 University Blvd., Vancouver, BC, Canada V6T the initial trauma, presents the first opportunity for 1Z4 intervention after SCI. Events that fall under the Orchestrating spinal cord repair LM Ramer et al 135 umbrella ofsecondary injury include vascular changes agent. Following SCI, systemic minocycline administra- (edema, ischemia, and hypoxia), excitotoxic biochemical tion has also been documented to inhibit microglial events (formation of free radicals and nitric oxide, activation, to promote oligodendrocyte survival, to protease release), and cellular responses (invasion by reduce lesion-induced cavity formation, and to prevent immune cells, activation ofglial cells, and death of the retraction or dieback ofinjured dorsal column, neurons and glia) (reviewed in Hausmann2). How rubrospinal, and corticospinal axons.18–20 The axonal significantly each component ofsecondary injury con- protection afforded by this treatment may be ofinterest, tributes to loss offunction remains unclear: what is since the rats also exhibit improved functional recov- evident is that the resulting pathology might be ery,18,19,21 although the restricted subtotal nature ofthe ameliorated by eliminating one or more ofthese players dorsal column lesion would permit neural plasticity in the early stages ofSCI. within preserved pathways to contribute to recovery. Clinical trials ofneuroprotective agents, delivered The mechanism by which sensory dorsal column axons acutely following SCI, have been carried out with dieback following injury may involve macrophage- equivocal success. The two most widely discussed are mediated degeneration ofproximal myelin sheaths, the National Acute Spinal Cord Injury Study (NASCIS) since in myelin-deficient rats macrophage/microglial trial ofhigh-dose systemic methylprednisolone (MP) 3 activation with zymosan does not induce axonal and the Sygens trial ofGM-1 gangliosides. 4 GM-1 retraction.20 Interestingly, suppression ofp75, a putative gangliosides appeared to enhance the rate ofrecovery signaling receptor for myelin inhibition, also reduced from SCI, but did not significantly improve the ultimate axonal retraction/dieback from the lesion site in p75 functional outcome, whereas MP was reported to knockout mice (p75À/À).22 This effect ofp75 deletion improve functional outcome when administered within was evident in pictures ofthe lesion site, although the 8 h ofSCI. 5 Although MP has since been widely used as authors ofthe study did not discuss reduced retraction/ a neuroprotective therapy, several more recent studies dieback as a result ofthis study. have reported equivocal benefits and concerns about the The loss ofneurons and glia at the site ofSCI is well- potential toxicity ofthe required high doses and documented. However, at more remote distances, the observed medical complications (reviewed by Kwon extent ofneuronal death following SCI has probably et al6). Administration ofthis steroid is no longer a been overestimated. Even 1 year after a cervical SCI, standard treatment, nor even a guideline for treatment, the cell bodies ofsevered descending rubrospinal ofacute SCI in Canada 7 and many other countries have axons, which were previously thought to have perished, adopted similar policies. regained normal neuronal morphology when BDNF In the midst ofcontroversy surrounding the use of was administered in the vicinity ofthe red nucleus. 23 currently available pharmacologic interventions, the Rather than being generated de novo, these rubrospinal search for an effective neuroprotective agent is ongoing neurons had atrophied to the point where they were in animal models ofSCI. Neuroprotective strategies easily missed during previous histological screens, have been reviewed at length previously.8,9 Here we leading to an underestimation oftheir numbers and focus on recent work from our group and elsewhere resulting in the premature declaration oftheir death. dealing with some ofthe neuronal consequences of Recently, adeno-associated viral (AAV) vector- secondary injury, including axonal retraction/dieback mediated BDNF gene transfer into the red nucleus and neuronal atrophy/death. similarly counteracted atrophy ofchronically lesioned One potential mechanism for secondary neuronal rubrospinal neurons.24 It is not known to what extent injury which is undergoing thorough investigation in a severe atrophy (rather than neuronal loss) is a general number oflaboratories involves endogenous (micro- response ofCNS neurons to chronic injury, but glial) or invading (hematogenous) phagocytic cells. corticospinal neurons also exhibit atrophy after spinal While the potential therapeutic use ofpreviously axotomy.25 IfSCI-induced atrophy is common among myelin-activated macrophages has received much atten- CNS neurons, it may mean that rather than attempting tion oflate (reviewed in; 10 see ‘Myelin and myelin to replace neurons through transplantation ofembryo- signaling’, below), several lines ofevidence demonstrate nic tissue or multipotent cells,26 therapies directed at that the microglial/macrophage response to SCI is reviving these ‘hibernating’ neurons may be more responsible for demyelination, oligodendrocyte death, appropriate. It has been observed that the direct CNS and damage to intact axons.11–14 The nontraumatic application of neurotrophic factors following SCI can injection ofthe micgroglia/macrophage activator zymo- prevent the atrophy ofrubrospinal, 27,28 cortico-
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