Intra spinal administration of Netrin-1 promotes locomotor recovery after complete spinal cord transection

QUINTA, HECTOR RAMIRO

JOURNAL OF NEUROTRAUMA.

MARY ANN LIEBERT INC

Año: 2021

0897-7151

Complete spinal cord lesions interrupt the connection of all axonal projections with their neuronal targets below and above of lesion site. In particular, the interruption of connections with the neurons at lumbar segments following thoracic injuries impairs voluntary body control below the injury. The failure of spontaneous re-growth of transected axons across the lesion prevents the re-connection and re-innervation of the neuronal targets. At present, the only treatment in humans that has proven to promote some degree of locomotor recovery is physical therapy. However, the success of these strategies greatly depends on the type of lesion and the level of preservation of neural tissue in the spinal cord after injury. That is why it is key to design strategies to promote axonal re-growth and neuronal re-connection. Here, we test the use of a developmental axon guidance molecule as a biological agent to promote axonal re-growth, axonal re-connection and recovery of locomotor activity after spinal cord injury (SCI). This molecule, Netrin-1, guides the growth of the Cortico-Spinal Tract (CST) during the development of the central nervous system. To assess the potential of this molecule we used a model of complete spinal cord transection in rats, at thoracic level 10-11 (Th10-11). We show that in-situ delivery of Netrin-1 at the epicenter of the lesion: (1) promotes re-growth of CST through the lesion and prevents CST die back, (2) promotes synaptic re-connection of regenerated motor and sensory axons, and (3) preserves the polymerization of the neurofilaments in the sciatic nerve axons. These anatomical findings correlate with a significant recovery of locomotor function. Our work identifies Netrin-1 as a biological agent with the capacity to promote the functional repair and recovery of locomotor function after SCI. These findings support the use of Netrin-1 as a therapeutic intervention to be tested in humans.