Anti-repulsive guidance molecule-a antibody treatment and repetitive transcranial magnetic stimulation have synergistic effects on motor recovery after spinal cord injury

Damaged axons in the adult central nervous system (CNS) fail to regenerate spontaneously due to several intrinsic and extrinsic factors that inhibit axon elongation. An extrinsic inhibitory factor, repulsive guidance molecule-a (RGMa), is upregulated around spinal cord lesion sites. Inhibition of RGMa using an antibody promotes axon sprouting, regeneration, and motor recovery after spinal cord injury (SCI) in rodents and primates. Repetitive transcranial magnetic stimulation (rTMS) has been used as a form of rehabilitation, and accumulating studies have suggested that rTMS is able to modulate neural plasticity of the cortex. Here, we conducted rTMS with anti-RGMa antibody treatment in mice with SCI to investigate the potential synergistic effects on motor recovery. Although mice treated with anti-RGMa antibody and rTMS concomitantly did not show significant motor recovery, mice treated sequentially with anti-RGMa antibody followed by rTMS showed better motor performance than mice treated with anti-RGMa antibody alone. Moreover, we found that Ca(2+)calmodulindependent kinase II (CaMKII) was upregulated in mice treated with anti-RGMa antibody and rTMS sequentially compared with mice received a single anti-RGMa antibody treatment. These results suggest that anti-RGMa antibody treatment and rTMS intervention have synergistic effects on motor recovery, and that the timing of rTMS intervention is a critical factor to maximize the effect of anti-RGMa antibody treatment. These interventions may provide new therapeutic strategies for promoting motor recovery after SCI.