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Axonal regeneration of neurons in the central nervous system, following trauma, inflammation or other pathological conditions, is significantly diminished due to a restrictive micro-environment. This is thought to be a major factor in limiting the extent of recovery after spinal cord injury. Several molecules that restrict axonal outgrowth have been identified, such as MAG, Nogo, chondroitin sulphate proteoglycans and semaphorin3A. It has been demonstrated that blocking some of these inhibitors can result in increased axonal regeneration. However, new projections alone are not sufficient for recovery; these projections must form appropriate synaptic connections to allow rewiring of the neuronal circuits that can re-establish the lost functions. The capacity to form and strengthen novel neural pathways, namely neuroplasticity, depends greatly upon activity-driven reinforcement – repetition is therefore key.

In a recent Molecular Brain study, Masaya Nakamura from the Keio University School of Medicine, Japan, and colleagues present a novel combinatorial approach to promote neuronal rewiring in rats subjected to spinal cord injury. They demonstrate that in addition to using pharmacological treatment to favour the regeneration of neuronal projections in the damaged area, intense physical activity was crucial for extensive functional recovery of hind limb motility.

The authors developed a novel drug delivery system using silicone sheets to efficiently  deliver the semaphorin 3A inhibitor, SM-345431, to treat the rats following spinal transection. In addition, rats were subjected to extensive treadmill training. Pharmacologically-promoted axonal regeneration significantly improved motor performance when combined with physical therapy. Although intense treadmill training did not modify the extent of axonal regeneration, it nonetheless significantly improved hind limb coordination and movement compared to rats that were treated with the semaphorin 3A inhibitor alone. Finally, re-transection of the initial lesion site only partially affected motor performance, indicating that functional recovery involved factors additional to axonal regeneration, such as the rewiring of local neural circuits involved in locomotion.

Although axonal regeneration in the central nervous system is very limited, neuroplasticity allows the rewiring of relevant neural circuits and has the potential to contribute to rehabilitation. This study highlights the importance of physical therapy in addition to pharmacological intervention, and presents a promising combinatorial approach to enhance motor performance after spinal cord injury.



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Rewiring of regenerated axons by combining treadmill training with semaphorin3A inhibition

Zhang L, Kaneko S, Kikuchi K, Sano A, Maeda M, Kishino A, Shibata S, Mukaino M et al.

Molecular Brain 2014, 7:14

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