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Oxidative DNA Damage in the Pathophysiology of Spinal Cord Injury: Seems Obvious, but Where Is the Evidence?
Elle E M Scheijen1, Sven Hendrix2, David M Wilson1
1Neurosciences, Biomedical Research Institute, Hasselt University, Agoralaan Building C, 3590 Diepenbeek, Belgium.
Abstract:
Oxidative stress occurs at various phases of spinal cord injury (SCI), promoting detrimental processes such as free radical injury of proteins, nucleic acids, lipids, cytoskeleton, and organelles. Oxidative DNA damage is likely a major contributor to the pathogenesis of SCI, as a damaged genome cannot be simply turned over to avert detrimental molecular and cellular outcomes, most notably cell death. Surprisingly, the evidence to support this hypothesis is limited. There is some evidence that oxidative DNA damage is increased following SCI, mainly using comet assays and immunohistochemistry. However, there is great variability in the timing and magnitude of its appearance, likely due to differences in experimental models, measurement techniques, and the rigor of the approach. Evidence indicates that 8-oxodG is most abundant at 1 and 7 days post-injury (dpi), while DNA strand breaks peak at 7 and 28 dpi. The DNA damage response seems to be characterized by upregulation of PCNA and PARP1 but downregulation of APEX1. Significant improvements in the analysis of oxidative DNA damage and repair after SCI, including single-cell analysis at time points representative for each phase post-injury using new methodologies and better reporting, will uncover the role of DNA damage and repair in SCI.
Insights
Oxidative DNA damage is a key factor in spinal cord injury (SCI) pathogenesis, but research is limited. Improved analysis methods are needed to understand DNA damage and repair roles in SCI recovery.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Spinal cord injury (SCI) involves oxidative stress, damaging cellular components like DNA.
- Oxidative DNA damage is hypothesized to significantly contribute to SCI pathogenesis and cell death.
- Current evidence linking oxidative DNA damage to SCI is limited and shows high variability.
Purpose of the Study:
- To review the current evidence on oxidative DNA damage following SCI.
- To highlight the need for improved methodologies in analyzing DNA damage and repair in SCI.
- To underscore the potential role of DNA damage and repair in SCI pathogenesis and outcomes.
Main Methods:
- Review of existing literature on oxidative DNA damage in SCI.
- Analysis of studies using comet assays and immunohistochemistry to detect DNA damage.
- Examination of DNA damage response markers such as 8-oxodG, DNA strand breaks, PCNA, PARP1, and APEX1.
Main Results:
- Oxidative DNA damage is increased after SCI, but timing and magnitude vary.
- Specific markers like 8-oxodG peak at 1-7 days post-injury (dpi), while DNA strand breaks peak at 7-28 dpi.
- The DNA damage response involves upregulation of PCNA and PARP1, and downregulation of APEX1.
Conclusions:
- Oxidative DNA damage is a significant factor in SCI, contributing to cell death.
- Variability in findings necessitates standardized and advanced analytical techniques.
- Further research using improved methodologies, including single-cell analysis, is crucial to elucidate the role of DNA damage and repair in SCI.
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