The Evolution of Chemokine Release Supports a Bimodal Mechanism of Spinal Cord Ischemia and Reperfusion Injury

Abstract

Background-Paraplegia remains a devastating complication of thoracic aortic surgery. The mechanism of the antecedent spinal cord ischemia and reperfusion injury (IR) remains poorly described. IR involves 2 injuries, an initial ischemic insult and subsequent inflammatory amplification of the injury. This mechanism is consistent with the clinical phenomenon of delayed onset paraplegia. This study sought to characterize the inflammatory response in the spinal cord after IR and hypothesized that this would support a bimodal mechanism of injury. Methods and Results-Male C57Bl/6 mice were subjected to 5 minutes of aortic arch and left subclavian occlusion with subsequent reperfusion to generate spinal cord ischemia. Functional outcomes were scored at 12-hour intervals. Spinal cords were harvested after 0, 6, 12, 18, 24, 36, and 48 hours of reperfusion. Cytokine levels were analyzed using a mouse magnetic bead-based multiplex immunoassay. Inflammatory chemokine concentrations (interleukin [IL]-1␤, IL-6, keratinocyte-derived cytokine, macrophage inflammatory protein-1␣, monocyte chemotactic protein-1, RANTES, and tumor necrosis factor-␣) peaked at 6 hours and 36 to 48 hours after reperfusion. Functional scores reflected initial gain in function with subsequent decline, inversely proportional to cytokine levels. Immunofluorescent staining demonstrated microglia activation at 12 and 48 hours. Conclusions-Spinal cord ischemia and reperfusion injury occurs in 2 phases, correlating to increases in inflammatory chemokines release and microglial activation. These observations chronologically parallel the too-common clinical syndrome of delayed-onset paraplegia. Understanding the molecular pathogenesis of this injury may allow future intervention to prevent this devastating complication. (Circulation. 2012;126[suppl 1]:S110 -S117.)

Dose-dependent protection of reseveratrol against spinal cord ischemic-reperfusion injury in rats

“…Compared with the SCIR-injured rats, the RESV and MP treatments substantially suppressed the concentrations of these pro-inflammatory cytokines, indicating their anti-inflammatory potential. Our results are supported by those of Smith et al, who evaluated inflammatory chemokine concentrations (interleukin-1β, IL-6 and TNF-α) and reported elevated levels of these inflammatory cytokines after SCIR [26]. Furthermore, RESV can effectively improve cerebral blood flow by crossing the blood-brain barrier and exhibits protective effects against ischemic injury by decreasing glial cell activation and thus positively alleviating oxidative stress and the inflammatory cascade.…”

Protective effects of Naringin in a rat model of spinal cord ischemia–reperfusion injury

“…The abovementioned biochemical analyses revealed that NAR attenuates the concentration of various inflammatory markers; to confirm these results, the protein expression of TNF-α and NF-κB p65 were quantified. Previous studies have revealed that the activation of NF-κB p65 is a crucial event during the induction of SCII in several animal models [3,27]. As indicated above, the protein expression of both TNF-α (cytosolic fraction) and NF-κB p65 (nuclear fraction) was significantly upregulated during SCII due to excessive oxidative stress and inflammation.…”

Photothrombosis-induced Focal Ischemia as a Model of Spinal Cord Injury in Mice

“…Few of the shortcomings include lack of an anatomically clear ischemic penumbra, which is the target of many neuroprotective drugs, and the absence of reperfusion. It is well known that reperfusion following ischemia is characterized by changes like increased production of reactive oxygen species, infiltration of inflammatory cells and increased cytokine production [30][31][32] . Lack of reperfusion in PT means the changes associated with reperfusion injury in SC will remain difficult to study using this model.…”