Endoplasmic Reticulum Stress is Involved in the Protective Effect of Sivelestat Sodium Hydrate (ONO-5046) in Spinal Cord Ischemia-Reperfusion Injury.

Abstract

Postoperative complications of thoracoabdominal aortic aneurysm include paraplegia due to impaired blood flow in the spinal cord. Sivelestat sodium hydrate (ONO-5046), a specific neutrophil elastase inhibitor, can prevent neuropathy after ischemia-reperfusion of the spinal cord; however, the underlying mechanism remains unclear. Here, we examined whether ONO-5046 elicits its protective effects in spinal cord ischemia by affecting endoplasmic reticulum (ER) stress. Forty-five male Japanese white rabbits (weight 2.5-3.0 kg) were assigned to three groups: a sham control group (n = 5), and two other groups (n = 20, respectively; n = 5 each time point) that were subjected to spinal cord ischemia-reperfusion for 15 min and administered saline or ONO-5046 intravenously. From 8 h to 7 d after resumption of blood flow, a neurological evaluation, histological evaluation of the spinal cord, and immunohistochemical evaluation based on the expression of GRP78 and caspase12 were performed. Rabbits treated with ONO-5046 had fewer functional deficits and more surviving motor neurons after ischemia than did rabbits in the saline and control groups. In rabbits treated with ONO-5046, histological findings of the spinal cord showed a high number of viable motor nerves, whereas induction of GRP78, an ER stress response-related protein, was prolonged. Furthermore, caspase12 expression was activated by excessive ER stress and was downregulated in rabbits treated with ONO-5046, as compared with that in rabbits administered saline. ONO-5046 exerts a protective effect on the spinal cord by relieving ER stress during spinal cord ischemia.