Interleukin-1 receptor antagonist attenuates the severity of spinal cord ischemic injury in rabbits

ObjectiveThoracic and thoracoabdominal aortic surgery is sometimes complicated by subacute or delayed paraplegia. Pro-inflammatory cytokine interleukin-1 (IL-1) β has been implicated in extensive inflammation and progressive neurodegeneration after ischemia. Using a rabbit model, we investigated the neuroprotective effects of IL-1 receptor antagonist (IL-1ra) in a temporal fashion.MethodsSpinal cord ischemia was induced by aortic cross-clamping in New Zealand White rabbits. The animals were assigned to three groups. Group C (n = 20) received saline (0.2-mL) and Group I (n = 20) received IL-1ra (200-μg/0.2-mL) intrathecally just after reperfusion. Group S (n = 3) underwent sham operation without aortic occlusion. We assessed the neuroprotective effects of IL-1ra by evaluating neurological function, histopathological changes, and in-situ terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL staining). We also measured the levels of Nitric Oxide (NO) and S100β in cerebrospinal fluid (CSF). Each evaluation was performed sequentially within 120 hours after reperfusion.ResultsGroup C showed progressive deterioration of motor function which became statistically significant from 48 hours after the onset of reperfusion (P < .05, P < .01, P < .001, P < .001 at 48, 72, 96, and 120 hours, respectively). Compared to Group C, a higher number of viable neurons was observed with less severe spinal cord injury in Group I (P < .01, .05 and .05 at 24, 72, and 120 hours, respectively). TUNEL-positive neurons were also significantly reduced by the administration of IL-1ra (P <.01 and .05 at 24, and 120 hours, respectively). The difference between Group C and Group I with regard to NO was significant at 72 and 120 hours (P < .05), while that in terms of S100β was significant only at 24 hours (P < .05).ConclusionsAdministration of IL-1ra attenuates spinal cord ischemic-reperfusion injury as evidenced by reducing both neuronal necrosis and apoptosis.

Clinical RelevanceThe present study explores the possibility of reducing subacute or delayed paraplegia after thoracoabdominal aortic surgery using a pharmacological agent that is already available for clinical use. IL-1 mediated inflammatory reaction after ischemic insult can be thought as one of the mechanisms responsible for delayed infarct expansion leading to subacute or delayed paraplegia. IL-1ra has known anti-inflammatory properties and was therefore expected to suppress such post-ischemic inflammatory reaction, if given at an appropriate time. The results of the present study indicate that IL-1-targetted anti-cytokine therapy can be a potentially useful strategy for the attenuation of neurological injury after spinal cord ischemia.