Numerous obstacles to successful regeneration of injured axons in the adult mammalian spinal cord exist. Consequently, a treatment strategy inducing axonal regeneration and significant functional recovery after spinal cord injury has to overcome these obstacles. The current study attempted to address multiple impediments to regeneration by using a combinatory strategy after complete spinal cord transection in adult rats: (1) to reduce inhibitory cues in the glial scar (chondroitinase ABC), (2) to provide a growth-supportive substrate for axonal regeneration [Schwann cells (SCs)], and (3) to enable regenerated axons to exit the bridge to re-enter the spinal cord (olfactory ensheathing glia). The combination of SC bridge, olfactory ensheathing glia, and chondroitinase ABC provided significant benefit compared with grafts only or the untreated group. Significant improvements were observed in the Basso, Beattie, and Bresnahan score and in forelimb/hindlimb coupling. This recovery was accompanied by increased numbers of both myelinated axons in the SC bridge and serotonergic fibers that grew through the bridge and into the caudal spinal cord. Although prominent descending tracts such as the corticospinal and reticulospinal tracts did not successfully regenerate through the bridge, it appeared that other populations of regenerated fibers were the driving force for the observed recovery; there was a significant correlation between numbers of myelinated fibers in the bridge and improved coupling of forelimb and hindlimb as well as open-field locomotion. Our study tests how proven experimental treatments interact in a well-established animal model, thus providing needed direction for the development of future combinatory treatment regimens.

The limited plastic and regenerative capabilities of axons in the adult mammalian CNS can be enhanced by the application of a monoclonal antibody (mAb), IN-1, raised against the myelin-associated neurite growth inhibitor Nogo-A. The aim of the present study was to investigate the effects of this treatment on the functional recovery of adult rats with a dorsal over-hemisection of the spinal cord. Directly after injury, half of the animals were implanted with mAb IN-1-secreting hybridoma cells, whereas the others received cells secreting a control antibody (anti-HRP). A broad spectrum of locomotor tests (open field locomotor) score, grid walk, misstep withdrawal response, narrow-beam crossing) was used to characterize locomotor recovery during the 5 weeks after the injury. In all behavioral tests, the recovery in the mAb IN-1-treated group was significantly augmented compared with the control antibody-treated rats. EMG recordings of flexor and extensor muscles during treadmill walking confirmed the improvement of the locomotor pattern in the mAb IN-1-treated rats; step-cycle duration, rhythmicity, and coupling of the hindlimbs were significantly improved. No differences between the two groups with regard to nociception were observed in the tail flick test 5 weeks after the operation. These results indicating improved functional recovery suggest that the increased plastic and regenerative capabilities of the CNS after Nogo-A neutralization result in a functionally meaningful rewiring of the motor systems.

The purpose of this review is to discuss the achievements and perspectives regarding rehabilitation of sensorimotor functions after spinal cord injury. In the first part we discuss clinical approaches based on neuroplasticity, a term referring to all adaptive and maladaptive changes within the sensorimotor systems triggered by a spinal cord injury. Neuroplasticity can be facilitated through the training of movements with assistance as needed, and/or by electrical stimulation techniques. The success of such training in individuals with incomplete spinal cord injury critically depends on the presence of physiological proprioceptive input to the spinal cord leading to meaningful muscle activations during movement performances. The addition of rehabilitation technology, such as robotic devices allows for longer training times and provision of feedback information regarding changes in movement performance. Nevertheless, the improvement of function by such approaches for rehabilitation is limited. In the second part, we discuss preclinical approaches to restore function by compensating for the loss of descending input to spinal networks following complete spinal cord injury. This can be achieved with stimulation of spinal networks or approaches to restore their descending input. Electrical and pharmacological stimulation of spinal neural networks is still in an experimental stage; and despite promising repair studies in animal models, translations to humans up to now have not been convincing. It is likely that combinations of techniques targeting the promotion of axonal regeneration and meaningful plasticity are necessary to advance the restoration of function. In the future, refinement of animal studies may contribute to greater translational success.