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

Neurospine, 2021 · DOI: https://doi.org/10.14245/ns.2040722.361 · Published: June 1, 2021

Spinal Cord Injury Genetics Regenerative Medicine & Stem Cells

Simple Explanation

Spinal cord injuries (SCIs) present with a litany of sequelae and long-term complications including loss of motor function, loss of organ and autonomic function, increased risk of pressure ulcers and pain, and even death. Regardless of the mechanism of primary insult incurred, secondary changes readily follow without immediate intervention which includes axonal degeneration and demyelination that can propagate both in an anterograde (Wallerian) and retrograde manner, affecting both the grey and white matter. Necroptosis can be initiated by a multitude of other signaling pathways as well including death receptors, protein kinase R, DNA-dependent activator of interferon regulatory factors, pattern recognition receptors (PRRs), in addition to TNF signaling which includes RIPK1/3.

Study Duration

Not specified

Participants

Not specified

Evidence Level

Level 5, Review Article

Key Findings

1
RIPK1 exhibits pleiotropic effects contributing to the exacerbation of SCI and sufficient evidence supports the therapeutic utility of RIPK1 inhibitors.
2
Recent studies suggest that RIPK3 inhibitor, GSK872, improves motor function and spinal cord edema in a SCI mouse model.
3
Their results showed that blocking MLKL using NSA prevented a decrease in mitochondrial membrane potential, ATP, glutathione, and superoxide dismutase levels and also prevented an increase in ROS and malondialdehyde levels.

Research Summary

Spinal cord injuries present with a complex series of molecular cascades that ultimately induce cell death of neurons and glia and excitotoxicity of astrocytes, limiting the effect of therapeutic intervention in these damaged regions. Further emphasis was placed on potential therapeutics to limit the degree of necroptosis, in particular inhibition of RIPK1/3 and mTOR to increase rates of autophagy while inhibiting the necroptotic pathway in order to preserve cell survival and promote recovery via reduced inflammation, gliosis, and cell death. Additional studies are necessary to investigate and develop therapeutics that successfully inhibit the necroptotic pathway and facilitate recovery following SCI.

Practical Implications

RIPK1 Inhibition as a Therapeutic Target

Given the shared pathophysiological mechanisms between SCI and other neurodegenerative diseases, targeting RIPK1 may prove effective in treating SCI.

RIPK3 Inhibition as a Potential Strategy

Selective inhibition of RIPK3 via administration of B-RAFV600E inhibitor dabrafenib may be a potential focus of investigation for treating SCI.

MLKL Inhibition as a Prevention Method

Blocking MLKL may provide an effective way of preventing secondary injury after SCI, particularly within the first 12 hours of injury.

Study Limitations

1
The combined pharmacological effects of RIPK1 and RIPK3 inhibitors have yet to be explored following coadministration.
2
These interventions have not been sufficiently studied in human models of SCI either, warranting further investigation in that regard.
3
Current therapeutics directed towards specifically inhibiting MLKL are limited.

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