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

Rer1-mediated quality control system is required for neural stem cell maintenance during cerebral cortex development.

Rer1 is a retrieval receptor for endoplasmic reticulum (ER) retention of various ER membrane proteins and unassembled or immature components of membrane protein complexes. However, its physiological functions during mammalian development remain unclear. This study aimed to investigate the role of Rer1-mediated quality control system in mammalian development. We show that Rer1 is required for the sufficient cell surface expression and activity of γ-secretase complex, which modulates Notch signaling during mouse cerebral cortex development. When Rer1 was depleted in the mouse cerebral cortex, the number of neural stem cells decreased significantly, and malformation of the cerebral cortex was observed. Rer1 loss reduced γ-secretase activity and downregulated Notch signaling in the developing cerebral cortex. In Rer1-deficient cells, a subpopulation of γ-secretase complexes and components was transported to and degraded in lysosomes, thereby significantly reducing the amount of γ-secretase complex on the cell surface. These results suggest that Rer1 maintains Notch signaling by maintaining sufficient expression of the γ-secretase complex on the cell surface and regulating neural stem cell maintenance during cerebral cortex development