Protective Effects Of SIV On Cerebral Ischemia-reperfusion Injury In Rats And Its Mechanism

Background and Aim To investigate the protective effect of SIV(Sivelestat sodium ,ONO-5046) on cerebral ischemia-reperfusion injury in rats and its mechanism. Cerebrovascular disease is the thirld disease which leads to disability and death for older persons, among which ischemic cerebrovascular disease is much more than 80%. Many studies and evidence indicated that inflammation induced by cerebral ischemia-reperfusion injury related with neutrophilic leukocyte( polymorphonuclear leukocyte, PMN) [1] . When activated by cerebral ischemia, neutrophil release elastase(NE) which take part in the process of the degradation of extracellular matrix components such as elastin, fibronectin and proteoglycan; and promote the movement of PMN to endodermis and the adhesion of PMN to the vascular endothelial cell , induce the damage of vascular endothelial cells and tissues.SIV (Sivelestat sodium ,ONO-5046) is a specific and competitive NE inhibitor in various species, On clinically, SIV (Sivelestat sodium , ONO-5046) was used to treat acute lung injury and respiratory distress syndrome[2] [3]. Recent research indicated that SIV(Sivelestat sodium , ONO-5046) could significantly alleviate ischemia-reperfusion injury of hepatic, myocardium, and spinal by inhibiting neutrophils priming[2-16], inhibiting NE release, reducing inflammatory mediators and improving energy after ischemia-reperfusion. and indicated that SIV(Sivelestat sodium , ONO-5046) have protective effect on the tissue and organic injuries especially induced by ischemia - reperfusion injury. So our study aim is to investigate the protective effect of SIV(Sivelestat , ONO-5046) on cerebral ischemia-reperfusion injury in rats and its mechanismMethods 90 rats were randomly divided into 6 groups: sham operation group , ischemia-reperfusion group and 10,30,90m g﹒kg–1 SIV(Sivelestat sodium, ONO-5046) groups,Nimodipine group (Nimodipine 1 mg﹒ kg–1) with 15 rats in each group. The model of focal cerebral ischemia-reperfusion in rats was established with modified sutured-occluded method. The rats in Siv groups were injected with SIV(Sivelestat sodium , ONO-5046) groups at the matched concentration .The rats in sham operation group and model group were injected with saline .And all rats were given more time in 3 hours , 6 hours after ischemia. Rats were sacrificed for histologic examination after the behavioral test, and their brains were taken to assay the activities of SOD,MDA, MPO,the content of NE and the expression of Caspase-1 (ICE) and caspase-3.Results and conclusion:(1) Sivelestat can inhibit NE releasing, lessen the cerebral edema and pathologic change and the phenomenon in a dose-dependent manner. It is indicated that SIV(Sivelestat sodium , ONO-5046) have protective effect on the cerebral ischemia-reperfusion injury in rats.(2) Sivelestat could markedly reduced the content of MDA, increased SOD activity, decreased MPO activity, and reduced the inflammatory mediators(Caspase-3,ICE) to normal. SIV (Sivelestatsodium,ONO-5046)can relive the cerebral ischemia-reperfusion injury, and its mechanism may be partly related to the effects of its antiinflammation and antioxidation . so we presumed that the protection of SIV(Sivelestat sodium,ONO-5046) from cerebral ischemia-reperfusion injury maybe related to those factors.