Tetanus toxin C-fragment protects against excitotoxic spinal motoneuron degeneration in vivo

The tetanus toxin C-fragment is a non-toxic peptide that can be transported from peripheral axons into spinal motoneurons. In in vitro experiments it has been shown that this peptide activates signaling pathways associated with Trk receptors, leading to cellular survival. Because motoneuron degeneration is the main pathological hallmark in motoneuron diseases, and excitotoxicity is an important mechanism of neuronal death in this type of disorders, in this work we tested whether the tetanus toxin C-fragment is able to protect MN in the spinal cord in vivo. For this purpose, we administered the peptide to rats subjected to excitotoxic motoneuron degeneration induced by the chronic infusion of AMPA in the rat lumbar spinal cord, a well-established model developed in our laboratory. Because the intraspinal infusion of the fragment was only weakly effective, whereas the i.m. administration was remarkably neuroprotective, and because the i.m. injection of an inhibitor of Trk receptors diminished the protection, we conclude that such effects require a retrograde signaling from the neuromuscular junction to the spinal motoneurons. The protection after a simple peripheral route of administration of the fragment suggests a potential therapeutic use of this peptide to target spinal MNs exposed to excitotoxic conditions in vivo.