Sequential therapy of anti-Nogo-A antibody treatment and treadmill training leads to cumulative improvements after spinal cord injury in rats

Abstract

Intense training is the most clinically successful treatment modality following incomplete spinal cord injuries (SCIs). With the advent of plasticity enhancing treatments, understanding how treatments might interact when delivered in combination becomes critical. Here, we investigated a rational approach to sequentially combine treadmill locomotor training with antibody mediated suppression of the fiber growth inhibitory protein Nogo-A. Following a large but incomplete thoracic lesion, rats were immediately treated with either anti-Nogo-A or control antibody (2weeks) and then either left untrained or step-trained starting 3weeks after injury for 8weeks. It was found that sequentially combined therapy improved step consistency and reduced toe dragging and climbing errors, as seen with training and anti-Nogo-A individually. Animals with sequential therapy also adopted a more parallel paw position during bipedal walking and showed greater overall quadrupedal locomotor recovery than individual treatments. Histologically, sequential therapy induced the greatest corticospinal tract sprouting caudally into the lumbar region and increased the number of serotonergic synapses onto lumbar motoneurons. Increased primary afferent sprouting and synapse formation onto lumbar motoneurons observed with anti-Nogo-A antibody were reduced by training. Animals with sequential therapy also showed the highest reduction of lumbar interneuronal activity associated with walking (c-fos expression). No treatment effects for thermal nociception, mechanical allodynia, or lesion volume were observed. The results demonstrate that sequential administration of anti-Nogo-A antibody followed in time with intensive locomotor training leads to superior recovery of lost locomotor functions, which is probably mediated by changes in the interaction between descending sprouting and local segmental networks after SCI.

Regenerative Therapies for Spinal Cord Injury

“…33 For example, Chen et al found that treatment of rats with anti-NOGO-A antibodies after incomplete thoracic SCI followed by treadmill locomotive training improved motor recovery. 208…”

Astrocyte-selective AAV-ADAMTS4 gene therapy combined with hindlimb rehabilitation promotes functional recovery after spinal cord injury

“…How exactly rehabilitation influences plasticity is not well understood, however, appropriate rehabilitation regimes can prove to be astonishingly effective. For example, task-specific rehabilitation combined with ChABC almost completely restored some motor tasks (Chen et al, 2017;Garcia-Alias et al, 2009). Furthermore, specifically training the hindlimbs using bipedal treadmill exercise after thoracic spinal cord injury significantly improved several parameters of motor functions when combined with the plasticity-promoting treatment, anti-Nogo-A antibody (Chen et al, 2017).…”

“…For example, task-specific rehabilitation combined with ChABC almost completely restored some motor tasks (Chen et al, 2017;Garcia-Alias et al, 2009). Furthermore, specifically training the hindlimbs using bipedal treadmill exercise after thoracic spinal cord injury significantly improved several parameters of motor functions when combined with the plasticity-promoting treatment, anti-Nogo-A antibody (Chen et al, 2017). Rehabilitation may enhance the ADAMTS4-induced improvements to behavioural scores that were shown by Tauchi and colleagues.…”

Evaluating the effectiveness of anti-Nogo treatment in spinal cord injuries

“…Recently it was observed once again that treatment with anti-Nogo followed by training was the most efficient strategy for increasing recovery after an incomplete thoracic lesion [43]. Climbing errors and paw dragging in rats were both reduced which is important as the CST is crucial in digit movement confirming its involvement in the recovery.…”