Role of necroptosis in traumatic brain and spinal cord injuries

Journal of Advanced Research, 2022 · DOI: https://doi.org/10.1016/j.jare.2021.12.002 · Published: December 22, 2022

Simple Explanation

Traumatic brain injury (TBI) and spinal cord injury (SCI) can cause severe sensory, motor, and autonomic nervous system dysfunctions, and effective treatments are still unavailable due to uncontrollable nerve cell death. Necroptosis, a type of programmed cell death, is a critical mechanism in neuronal cell death, involving receptor-interacting protein kinases (RIPKs) and mixed lineage kinase domain-like protein (MLKL). This review summarizes necroptosis's role in central nervous system (CNS) trauma, its therapeutic implications, and provides suggestions for in-depth research, highlighting agents capable of curtailing cell death after CNS trauma.

Study Duration

Not specified

Participants

Not specified

Evidence Level

Review

Key Findings

1
RIPK1, RIPK3, and MLKL expression increases in the hours to days after TBI, but the temporal patterns of these proteins differ between SCI and TBI.
2
Molecular targets mediating necroptosis and potential treatment strategies vary among different cell types (neurons, astrocytes, microglia/macrophages) in CNS trauma.
3
MicroRNAs (miRNAs) regulate necroptosis involved in CNS trauma; for example, miR-223-3p binds to the 30-UTR of RIPK3 mRNA and negatively regulates the RIPK3 necroptotic signalling pathway.

Research Summary

This review provides an overview of the necroptosis signaling pathway and execution in the context of CNS trauma. The review discusses the temporal pattern of RIPK1/3 expression following CNS trauma, noting slight differences in the peak phases of RIPK1/3 and MLKL expression between TBI and SCI. The review also highlights potential agents that can block necroptosis and suggests future research directions, including the regulatory mechanisms of RIPK1 and MLKL, the role of MLKL in nonnecroptotic functions, and the stoichiometry of necroptotic MLKL oligomers.

Practical Implications

Therapeutic Target Identification

Targeting necroptosis and its key proteins (RIPK1, RIPK3, MLKL) could offer novel therapeutic strategies for TBI and SCI.

Cell-Specific Treatments

Developing cell-specific therapies that target necroptosis in different cell types (neurons, astrocytes, microglia) may improve treatment outcomes.

MicroRNA-Based Therapies

Exploring the potential of miRNAs to regulate necroptosis could lead to new therapeutic interventions for CNS trauma.

Study Limitations

1
The regulatory mechanisms of RIPK1 and MLKL in CNS trauma are not fully understood.
2
The role of MLKL in nonnecroptotic functions following CNS trauma has not been determined.
3
The stoichiometry of necroptotic MLKL oligomers remains contentious.

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