Oxidative DNA Damage in the Pathophysiology of Spinal Cord Injury: Seems Obvious, but Where Is the Evidence?

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.

Lentivirus-mediated knockdown of Ski inhibits glial scar formation and promotes axonal regeneration and functional recovery after spinal cord injury in rats

“…After spinal cord injury, the different microenvironments in which neurons and various supporting cells are located during each time period result in different pathophysiological changes occurring at the injury site during different time periods. In the acute phase, the destruction of the spinal cord microvasculature due to mechanical injury causes massive cell degeneration and necrosis, and the necrotic cells release large amounts of cytokines into the site of injury [8], this leads to a series of pathophysiological changes, including: free radical production, lipid peroxidation, in ammation, and necrotic cell death [9][10][11][12]. The subacute phase lasts up to 2 weeks, during which a series of glial cells, including astrocytes, microglia and oligodendrocytes, are stimulated by cytokines to proliferate and migrate to the site of spinal cord injury due to the dramatic changes in the cellular microenvironment of the injured spinal cord [13].…”

Astaxanthin promotes locomotor function recovery and attenuates tissue damage in rats following spinal cord injury: a systematic review and trial sequential analysis

“…Tissue structure and homeostasis are broken down instantly following the primary insult induced by trauma or ischemia. Subsequently, the secondary damage phase, involving oxidative stress, dysregulation of ion flow, neurotransmitter toxicity, immune cell activation, and neuronal loss, is gradually triggered ( Liu et al, 2021 ; Salvador and Kipnis, 2022 ; Scheijen et al, 2022 ). Among these changes, oxidative stress is demonstrated to be triggered in just a few hours after initial injury ( Liu et al, 2004 ; Tran et al, 2018 ).…”

Oxidative DNA Damage and Repair: Mechanisms, Mutations, and Relation to Diseases

“…Spinal cord injury (SCI) is the damage to the spinal cord resulting from either trauma or pathology (e.g., cancer). SCI is a severely debilitating neurological disorder which affects up to 500,000 people worldwide annually [ 16 ]. Oxidative stress plays a hallmark role in pathophysiology of SCI.…”

“…Oxidative stress plays a hallmark role in pathophysiology of SCI. Although it would be natural to assume that the consequent oxidative DNA damage is a major contributor to the pathogenesis of SCI, there is surprisingly little experimental evidence supporting this assumption, as reflected in the review by Scheijen et al [ 16 ]. There is an agreement among researchers that oxidative DNA damage increases after SCI, primarily by using comet assays and immunohistochemistry.…”

“…There is very little data on DNA repair mechanisms in response to SCI, and only a few repair components have been assessed, such as PCNA, PARP1, and APEX1. Evidently, many gaps in knowledge of DNA damage and repair during SCI must be filled in future studies [ 16 ].…”