Novel Methods of Necroptosis Inhibition for Spinal Cord Injury Using Translational Research to Limit Secondary Injury and Enhance Endogenous Repair and Regeneration

Spinal cord injuries (SCIs) pose an immense challenge from a clinical perspective as current treatments and interventions have been found to provide marginal improvements in clinical outcome (with varying degrees of success) particularly in areas of motor and autonomic function. In this review, the pathogenesis of SCI will be described, particularly as it relates to the necroptotic pathway which has been implicated in limiting recovery of SCI via its roles in neuronal cell death, glial scarring, inflammation, and axonal demyelination and degeneration. Major mediators of the necroptotic pathway including receptor-interacting protein kinase 1, receptor-interacting protein kinase 3, and mixed-lineage kinase domain-like will be described in detail regarding their role in facilitating necroptosis. Additionally, due to the rapid accumulation of reactive oxygen species and inflammatory markers, the onset of necroptosis can begin within hours following SCI, thus developing therapeutics that readily cross the blood-brain barrier and inhibit necroptosis during these critical periods of inflammation are imperative in preventing irreversible damage. As such, current therapeutic interventions regarding SCI and targeting of the necroptotic pathway will be explored as will discussion of potential future therapeutics that show promise in minimizing long-term or permanent damage to the spinal cord following severe injury.