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

Abstract

Spinal cord injuries (SCI) 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 RIPK1, RIPK3, and MLKL will be described in detail regarding their role in facilitating necroptosis. Additionally, due to the rapid accumulation of reactive oxygen species (ROS) and inflammatory markers, the onset of necroptosis can begin within hours following SCI, thus developing therapeutics that readily cross the blood-brain barrier (BBB) 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.

The Effects of the Combination of Mesenchymal Stromal Cells and Nanofiber-Hydrogel Composite on Repair of the Contused Spinal Cord

“…Mechanistically, the primary insult triggers a series of molecular and cellular cytotoxic events that, in concert, cause further nervous tissue damage and degeneration [ 1 , 2 ]. Protecting nervous tissue from secondary damage is an important early line of defense to limit the devastating consequences of SCI [ 42 ]. We found that MSC and NHC both have neuroprotective effects that limit injury expansion in the spinal cord.…”

Established and Emerging Therapies in Acute Spinal Cord Injury

“…91 The process is dependent on receptor-interacting serine/threonine kinase 1 and 3 and studies have shown that it may be one of the primary forms of cell death following trau-matic SCI. 91 Inhibition of this pathway is suspected to attenuate secondary damage and minimize cell death. 92 Autologous omental transplantation has been proposed as a method to introduce blood-and lymph-rich tissue to injured spinal cord tissue.…”

Fabrication Techniques of Nerve Guidance Conduits for Nerve Regeneration

“… 8 9 10 11 Disruption of spinal cord blood vessels induces hemorrhage and ischemia at the SCI site. 12 13 14 In addition, excessive activated chemicals, such as the excitatory neurotransmitters glutamate or aspartate, cause damage to neurons, astrocytes, and oligodendrocytes. As a result, damage to oligodendrocytes leads to axonal demyelination, which impairs nervous system plasticity.…”