The Neuroprotective Effects Of Locally Intra-arterial Edaravone Infusion In Acute Cerebral Infarction Rats Models

Objective: Locally intra-arterial drug administration has the advantages of low dose,effective drug concentration and less systemic side effect.The present study was designed to explore the neuroprotective effect of locally intra-arterial Edaravone infusion in acute cerebral infarction rat model recently developed by us,and investigate the role of MAPK signal transduction pathway in the neuroprotective effect.Method: Middle cerebral artery occlusion(MCAO)was induced in Sprague-Dawley rats.Animals were randomly divided into intra-arterial groups and intra-venous groups.The intra-arterial groups were made by the microcatheter device,which was used to pour the Edaravone into infarction region.The intra-venous groups were made by monofilament nylon suture and give Edaravone via caudal vein.In order to investigate the dose dependent effect of Edaravone administration,3 different doses were intra-arterial delivered at 1h or 2h separately: 0.5 mg/kg,1.5 mg/kg,3.0 mg/kg;while 3different doses were intra-venous administration: 1.5 mg/kg,3.0 mg/kg,10.0mg/kg,delivery time were same with intra-arterial groups.The dose dependent effect of Edaravone on infarct volume,neurological deficit,and TUNEL staining were determined.To investigate the effect of the arterial administration on the therapeutic time window,3 subgroups were further divided according to different time points: 1 h,2h,3 h groups.0.5mg/kg Edaravone was given via intra-arterial administration,while3mg/kg Edaravone was given via intra-venous administration.The effect of Edaravoneat different time points on the infarct sizes,neurological deficit,and motor behavior(foot-fault placing test,parallel-bar crossing test,rope climbing test)was investigated.In order to investigate the mechanism underlying the neuroprotective effect,MAPK expression was measured at different time points(1 h,2 h,3 h)following intra-arterial or intra-venous injection of Edaravone or Vehicle by western blot.Results: For the dose groups,all the intra-arterial groups with different doses(0.5mg/kg,1.5 mg/kg,3.0 mg/kg)markedly decreased the infarct size,improved neurological deficits and reduced TUNEL-positive apoptotic cells,and show dose-dependent effect.Compare to that of intra-artery groups,intra-venous groups with different doses(1.5 mg/kg,3.0 mg/kg,10.0 mg/kg)will need much higher dose to reach the same curative affection.Given the side of high dose of Edaravone,intra-arterial administration has the advantage of low therapeutic dose.For the effect of therapeutic time window,intra-arterial Edaravone infusion at 1h or 2h after MCAO can significantly decreased the infarct size,improved neurological deficits and motor behavior.While the intra-venous Edaravone only show the neuroprotective effect at 1h after MCAO.The rusults further demonstrate that locally intra-arterial Edaravone can extends its therapeutic time window.After MCAO,the oxidative stress injury will activate the MAPK pathway.The JNK expression quantity at each time point of infarct group presented with progressive tendency.Compared to the intra-venous groups,locally intra-arterial Edaravone have more inhibitory effect on the JNK expression.Conclusion: Locally intra-artirial Edaravone infusion,not only can reduce the dose of drug,but also prolong the therapeutic time window.The neuroprotective mechanism of Edaravone may be related to the MAPKsignal transduction pathway.