Exercise after spinal cord injury as an agent for neuroprotection, regeneration and rehabilitation.

Spinal cord injury (SCI) is a traumatic event from which there is limited recovery of function, despite the best efforts of many investigators to devise realistic therapeutic treatments. Partly this is due to the multifaceted nature of SCI, where there is considerable disarray and dysfunction secondary to the initial injury. Contributing to this secondary degeneration is neurotoxicity, vascular dysfunction, glial scarring, neuroinflammation, apoptosis and demyelination. It seems logical that addressing the need for neuroprotection, regeneration and rehabilitation will require different treatment strategies that may be applied at varied stages of the post-injury response. Here we focus on a single strategy, exercise/physical training, which appears to have multiple applications and benefits for an acute or chronic SCI. Exercise has been demonstrated to be advantageous at cellular and biochemical levels, as well as being of benefit for the whole animal or human subject. Data from our lab and others will be discussed to further elucidate the many positive aspects of implementing exercise following injury and to suggest that rehabilitation is not the sole target of a training regimen following SCI. This article is part of a Special Issue entitled SI: Spinal cord injury.

Exogenous BDNF enhances the integration of chronically injured axons that regenerate through a peripheral nerve grafted into a chondroitinase-treated spinal cord injury site.

Although axons lose some of their intrinsic capacity for growth after their developmental period, some axons retain the potential for regrowth after injury. When provided with a growth-promoting substrate such as a peripheral nerve graft (PNG), severed axons regenerate into and through the graft; however, they stop when they reach the glial scar at the distal graft-host interface that is rich with inhibitory chondroitin sulfate proteoglycans. We previously showed that treatment of a spinal cord injury site with chondroitinase (ChABC) allows axons within the graft to traverse the scar and reinnervate spinal cord, where they form functional synapses. While this improvement in outgrowth was significant, it still represented only a small percentage (<20%) of axons compared to the total number of axons that regenerated into the PNG. Here we tested whether providing exogenous brain-derived neurotrophic factor (BDNF) via lentivirus in tissue distal to the PNG would augment regeneration beyond a ChABC-treated glial interface. We found that ChABC treatment alone promoted axonal regeneration but combining ChABC with BDNF-lentivirus did not increase the number of axons that regenerated back into spinal cord. Combining BDNF with ChABC did increase the number of spinal cord neurons that were trans-synaptically activated during electrical stimulation of the graft, as indicated by c-Fos expression, suggesting that BDNF overexpression improved the functional significance of axons that did reinnervate distal spinal cord tissue.

PEGylated interferon-beta modulates the acute inflammatory response and recovery when combined with forced exercise following cervical spinal contusion injury.

Secondary degeneration leads to an expansion of the initial tissue damage sustained during a spinal cord injury (SCI). Dampening the cellular inflammatory response that contributes to this progressive tissue damage is one possible strategy for neuroprotection after acute SCI. We initially examined whether treatment with a PEGylated form of rat interferon-beta (IFN-beta) would modulate the expression of several markers of inflammation and neuroprotection at the site of a unilateral cervical level 5 contusion injury. Adult female Sprague-Dawley rats were injured using the Infinite Horizon Impactor at a force of 200 kdyn (equivalent to a severe injury) and a mean displacement of 1600-1800 mum. A single dose (5x10(6) units) of PEGylated IFN-beta or vehicle was administered 30 min following SCI. Here we demonstrate temporal changes in pro- and anti-inflammatory cytokine levels and the expression of heat shock proteins and iNOS (involved in neuroprotection) at the lesion epicenter and one segment caudally after SCI and PEG IFN-beta treatment. The results suggested a potential therapeutic treatment strategy for modulation of secondary damage after acute SCI. Therefore, we examined whether acute treatment with PEG IFN-beta would improve forelimb function alone or when combined with forced exercise (Ex). Animals began the Ex paradigm 5 days post SCI and continued for 5 days/week over 8 weeks. Locomotion (forelimb locomotor scale [FLS], hindlimb BBB, and TreadScan) and sensorimotor function (grid walking) was tested weekly. Additional outcome measures included lesion size and glial cell reactivity. Significant FLS improvements occurred at 1 week post SCI in the PEGylated IFN-beta-treated group but not at any other time point or with any other treatment approaches. These results suggest that this acute neuroprotective treatment strategy does not translate into long term behavioral recovery even when combined with forced exercise.

Combining peripheral nerve grafts and chondroitinase promotes functional axonal regeneration in the chronically injured spinal cord.

Because there currently is no treatment for spinal cord injury, most patients are living with long-standing injuries. Therefore, strategies aimed at promoting restoration of function to the chronically injured spinal cord have high therapeutic value. For successful regeneration, long-injured axons must overcome their poor intrinsic growth potential as well as the inhibitory environment of the glial scar established around the lesion site. Acutely injured axons that regenerate into growth-permissive peripheral nerve grafts (PNGs) reenter host tissue to mediate functional recovery if the distal graft-host interface is treated with chondroitinase ABC (ChABC) to cleave inhibitory chondroitin sulfate proteoglycans in the scar matrix. To determine whether a similar strategy is effective for a chronic injury, we combined grafting of a peripheral nerve into a highly relevant, chronic, cervical contusion site with ChABC treatment of the glial scar and glial cell line-derived neurotrophic factor (GDNF) stimulation of long-injured axons. We tested this combination in two grafting paradigms: (1) a peripheral nerve that was grafted to span a chronic injury site or (2) a PNG that bridged a chronic contusion site with a second, more distal injury site. Unlike GDNF-PBS treatment, GDNF-ChABC treatment facilitated axons to exit the PNG into host tissue and promoted some functional recovery. Electrical stimulation of axons in the peripheral nerve bridge induced c-Fos expression in host neurons, indicative of synaptic contact by regenerating fibers. Thus, our data demonstrate, for the first time, that administering ChABC to a distal graft interface allows for functional axonal regeneration by chronically injured neurons.

Forced exercise as a rehabilitation strategy after unilateral cervical spinal cord contusion injury.

Evaluation of locomotor training after spinal cord injury (SCI) has primarily focused on hind limb recovery, with evidence of functional and molecular changes in response to exercise. Since trauma at a cervical (C) level is common in human SCI, we used a unilateral C4 contusion injury model in rats to determine whether forced exercise (Ex) would affect spinal cord biochemistry, anatomy, and recovery of fore and hind limb function. SCI was created with the Infinite Horizon spinal cord impactor device at C4 with a force of 200 Kdyne and a mean displacement of 1600-1800 microm in adult female Sprague-Dawley rats that had been acclimated to a motorized exercise wheel apparatus. Five days post-operatively, the treated group began Ex on the wheel for 20 min per day, 5 days per week for 8 weeks. Wheel speed was increased daily according to the abilities of each animal up to 14 m/min. Control rats were handled daily but were not exposed to Ex. In one set of animals experiencing 5 days of Ex, there was a moderate increase in brain-derived neurotrophic factor (BDNF) and heat shock protein-27 (HSP-27) levels in the lesion epicenter and surrounding tissue. Long-term (8 weeks) survival groups were exposed to weekly behavioral tests to assess qualitative aspects of fore limb and hind limb locomotion (fore limb scale, FLS and BBB [Basso, Beattie, and Bresnahan locomotor rating scale]), as well as sensorimotor (grid) and motor (grip) skills. Biweekly assessment of performance during wheel walking examined gross and fine motor skills. The FLS indicated a significant benefit of Ex during weeks 2-4. The BBB test showed no change with Ex at the end of the 8-week period, however hind limb grid performance was improved during weeks 2-4. Lesion size was not affected by Ex, but the presence of phagocytic and reactive glial cells was reduced with Ex as an intervention. These results suggest that Ex alone can influence the evolution of the injury and transiently improve fore and hind limb function during weeks 2-4 following a cervical SCI.