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Cell death in models of spinal cord injury
Michael S Beattie1, Gerlinda E Hermann, Richard C Rogers
1Department of Neuroscience, The Ohio State University Medical Center, 333 W. 10th Avenue, Columbus, OH 43210, USA. beattie.2@osu.edu
Abstract:
Current treatments for acute spinal cord injury are based on animal models of human spinal cord injury (SCI). These models have shown that the initial traumatic injury to cord tissue is followed by a long period of secondary injury that includes a number of cellular and biochemical cascades. These secondary injury processes are potential targets for therapies. Continued refinement of rat and mouse models of SCI, along with more detailed analyses of the biology of the lesion in these models, points to both necrotic and apoptotic mechanisms of cell death after SCI. In this chapter, we review recent evidence for long-term apoptotic death of oligodendrocytes in long tracts undergoing Wallerian degeneration following SCI. This process appears to be related closely to activation of microglial cells. It is has been thought that microglial cells might be the source of cytotoxic cytokines, such as tumor necrosis factor-alpha (TNF-alpha), that kill oligodendrocytes. However, more recent evidence in vivo suggests that TNF-alpha by itself may not induce necrosis or apoptosis in oligodendrocytes. We review data that suggests other possible pathways for apoptosis, such as the neurotrophin receptor p75 which is expressed in both neurons and oligodendrocytes after SCI in rats and mice. In addition, it appears that microglial activation and TNF-alpha may be important in acute SCI. Ninety minutes after a moderate contusion lesion, microglia are activated and surround dying neurons. In an 'atraumatic' model of SCI, we have now shown that TNF-alpha appears to greatly potentiate cell death mediated by glutamate receptors. These studies emphasize that multiple mechanisms and interactions contribute to secondary injury after SCI. Continued study of both contusion models and other new approaches to studying these mechanisms will be needed to maximize strategies for acute and chronic therapies, and for neural repair.
Insights
Secondary injury after spinal cord injury (SCI) involves cell death, including apoptosis of oligodendrocytes. Microglial activation and tumor necrosis factor-alpha (TNF-alpha) play complex roles, potentially interacting with glutamate receptors to influence cell death.
Area of Science:
- Neuroscience
- Cell Biology
- Pathology
Background:
- Spinal cord injury (SCI) triggers secondary injury cascades.
- Animal models are crucial for understanding SCI pathophysiology.
- Cell death, including necrosis and apoptosis, is a hallmark of SCI.
Purpose of the Study:
- To review evidence for oligodendrocyte apoptosis in SCI.
- To explore the role of microglial activation and TNF-alpha in SCI-induced cell death.
- To investigate alternative apoptotic pathways, such as p75 neurotrophin receptor signaling.
Main Methods:
- Analysis of rat and mouse models of SCI.
- Investigation of cellular and biochemical cascades post-injury.
- Examination of microglial activation and cytokine expression (TNF-alpha).
Main Results:
- Oligodendrocyte apoptosis occurs long-term in Wallerian degeneration post-SCI.
- Microglial activation is observed early after SCI, surrounding dying neurons.
- TNF-alpha may potentiate glutamate receptor-mediated cell death, rather than directly inducing apoptosis.
Conclusions:
- Multiple interacting mechanisms contribute to secondary SCI.
- Oligodendrocyte apoptosis is a significant factor in SCI pathology.
- Further research into SCI mechanisms is vital for developing effective therapies.