Full understanding of the complex mechanisms that lead to neuronal death after a spinal cord lesion is important to devise neuroprotective treatments. Amongst the factors proposed to strongly contribute to neuronal loss is the substantially raised concentration of extracellular glutamate, the main excitatory neurotransmitter, evoked by excitotoxic damage. This process is thought to be linked to the onset of the secondary injury that can amplify the initial damage to distant areas of the spinal cord. At SISSA, Trieste, a model that mimics the early pathological processes caused by traumatic injury has recently been developed to follow up its time-dependent evolution. This model allowed us to demonstrate that excitotoxicity-induced by the glutamate primarily destroyed neurons via a process slowly developing over a few hours. However, the neuroprotection strategies with several inhibitors of cell death pathways have been disappointing in terms of histological and functional outcome, thus pointing to additional death mechanisms. During my presentation I will discuss: 1. the main cell targets essential for locomotor patterns upon this pathological condition; 2. use of pharmacological drugs to protect against damage; 3. the endogenous neuroprogenitor cell proliferation induced by a pathological condition; 4. the early biomarkers to follow the progression; 5. importance of cell death spatio-temporal dynamic map to follow topographical and topological extension with an impact on locomotor function. 6. The surprising non-linear relation between neuronal death and locomotor network output. Using a multidisciplinary approach, new data can be obtained with high translational value for in vivo or clinical studies in the spinal cord field, and is a subject that will benefit from tailor-made modelling with predictive value for further scientific inquiry.