Expression of inflammatory cytokines following acute spinal cord injury in a rodent model

Abstract

Many therapies that have been developed for acute spinal cord injury (SCI) either influence or are influenced by posttraumatic inflammation. Many such therapies have reportedly produced promising neurologic benefits in animal models of SCI, but demonstrating convincing efficacy in human clinical trials has remained elusive. This discrepancy may be related in part to differences in the inflammatory response to SCI between human patients and the widely studied rodent models. Our objectives were, therefore, to establish the time course of inflammatory cytokine release in the spinal cord of rats after a thoracic contusion, to determine whether the cytokine release was injury dependent, and to correlate these findings with those that we have recently reported for the cerebrospinal fluid (CSF) of human SCI patients. After rodent SCI, GRO (the rat equivalent of IL-8), IL-6, IL-1α, IL-1β, IL-13, MCP-1, MIP1α, RANTES, and TNFα were elevated within the spinal cord, whereas IL-12p70 was decreased. In human SCI, IL-6, IL-8, and MCP-1 were also elevated within the cerebrospinal fluid but at later times than those observed in the rodent spinal cord. IL-6, IL-8, and MCP-1 were released in an injury-dependent manner in both the rodent model of SCI and the human condition. In this regard, similar patterns of expression were observed for a number of inflammatory cytokines after SCI in rodent spinal cords and in human CSF. Such proteins may therefore have potential utility as biomarkers and surrogate outcome measures for evaluating biological response to therapeutic interventions.

Cerebrospinal Fluid Inflammatory Cytokines and Chemokines in Naturally Occurring Canine Spinal Cord Injury

“…13 In the spinal cord of dogs with IVDH, IL-6 mRNA has been shown to be increased after acute SCI and IL-6 protein has been found to be overexpressed in rodent contusion models. 9,20,25 IL-18 and IP-10 have not been previously examined as mediators of injury in dogs with SCI and were decreased in affected animals in this study, compared to control animals. In rodent models of injury, IP-10 and IL-18 has been shown to be increased after SCI, and in humans, CSF IP-10 was increased beyond reference concentrations.…”

“…In humans, expression of CSF or spinal cord IL-8 peaks within 24 h of SCI, likely arises from a variety of local sources, including activated microglia, and has been associated with neutrophilic infiltration into parenchyma. 16,20 In the population studied here, increases in CSF nucleated cell count were uncommonly noted (18%; 7 of 39 dogs), but, when present, had a substantial neutrophilic component. In a previous study that examined mRNA expression of cytokines in the spinal cord of dogs with IVDH-associated SCI, IL-8 was likewise found to be increased, compared to control dogs, especially in acute injury.…”

“…In rodents with experimental SCI, peak CSF IL-6 concentration occurs only 6 h after injury and samples obtained 24 h after SCI had IL-6 concentration that was not significantly different than sham-treated animals. 20 We assessed relationships between CSF analytes and cytokine/ chemokine concentrations in dogs with SCI to better understand pathologic processes associated with cytokine and chemokine upregulation. Both MCP-1 and KC-like protein concentration in the CSF were positively correlated with CSF microprotein concentration, and MCP-1 was positively correlated with RBC concentration.…”

“…Similar increases in spinal cord tissue MCP-1 protein and mRNA have been reported in rodents with experimental spinal cord contusion. 20,27 CSF MCP-1 concentration was associated with neurological outcome at 42 days post-SCI, as measured by a validated ordinal score. However, no other cytokines or chemokines were associated with either initial SCI severity or 42-day post-SCI ordinal injury score.…”

Delayed Post-Injury Administration of Riluzole Is Neuroprotective in a Preclinical Rodent Model of Cervical Spinal Cord Injury

“…Studies examining inflammatory biomarkers after SCI in rodents and human patients suggest many crucial biomarkers are altered earlier in rodents compared to humans. 36,37 For example, the inflammatory cytokine, IL-6, is increased at 4 h post-SCI in rodents, while this cytokine only peaks at 24-32 h in human subjects. This suggests a difference of 4-6 hours between rodent and human SCI pathology.…”