The Experimental Study Of Therapeutic Time Window Of Neuregulin On Erebral Ischemia Reperfusion Injury

Objective To study the protective effect of Neuregulin-1β(NRG-1β) on the models with middle cerebral artery occlusion and reperfusion(MCAO/R) in rats,and search the perfect time to precauting brain injured.Then further to study interfering effect of NRG-1βon the cerebral ischemic reperfusion injury in monkeys.Methods(1) To establish the MCAO/R model with a suture blocking in the MCA in 200 adult healthy Wistar rats,then inject NRG-1βthrough the internal carotid artery(ICA) for therapy. Model function was evaluated by neurology score with Longa method,brain water content in ischemic brain tissure with dry-humid weight method,volume percentage of the cerebral infarction with tetrazolium chloride(TTC) stainand method,cell apoptosis by TUNEL way,different level of aquaporin-4(AQP-4) through immunohistochemistry technique and inmumofluorescence method.(2) The models with middle cerebral artery occlusion reperfusion(MCAO/R) were established by inserting a micro-balloon catheter intra-arterially into MCA from the femoral artery in 12 adult healthy monkeys.The NRG-1βwas injected into MCA from micro-balloon catheter in the animals of treatment group at ischemia 2h,while the normal saline was injected in the animals of control group at same tine.Then the micro-balloon catheter was withdrawn from the MCA to perfuse for 22h.The nervous behavioral function was evaluated by task-oriented score,the infarct volume was measured by TTC and MRI.Results(1) After the model was established, rats in control are all showed loss of function for nerve system,enhancement in brain water content(BWC) and the volume percentage of cerebral infarction,cell apotosis and level of AQP-4(P＜0.05).Such indexs are improved obviously in the treatment,and 1h time point may be the best one(P＜0.01).(2) The animals of control group appeared nervous functional disorders at cerebral ischemia 2h and had no significant difference at reperfusion 22h;the nervous function of monkeys was not improved after NFG-1βtreatment(P＞0.05).The diffuse weight imaging(DWI) shown high signal area but T₁ and T₂ imaging had no significant changes at cerebral ischemia 2h in control group animals;while the T₁ and T₂ imaging shown typical high signal areas,DWI high signal area enlarged,and TTC staining ischemic area at reperfusion 22h.The T₁,T₂ and DWI abnormal signal areas and TTC cerebral infarct volume did not shrink significantly in NFG-1βtreatment group(P＞0.05).Conclusion(1) NRG-1βhas some protection to the injurement of cerebral artery occlusion and reperfusion in rats,the time point of 1h occlusion may be the best therapeutic time window for it.(2) The neuroprotective effect of NRG-1βon cerebral ischemic reperfusion injury in rhesus monkey needs to be further researched.