Neuroprotective Effects Of Gene Recombination Neuregulin On Ischemic Cerebral Injury In Rats

Objective The aim is to investigate the precaution and the treatment effects ofNeuregulin-1β(NRG-1β)on the middle cerebral artery occlusion (MCAO)injury in rats,toexplore the pathophysiology mechanism of brain damage,the perfect therapeutic time andthe neuroprotection of NRG-1βin rats after MCAO.Methods Four hundred and seventy-five MCAO animal models were establishedwith a suture and randomly designed into a sham-operation group,a control group,apretreatment group and a treatment group.NRG-1βwas administrated through theexternal-internal carotid artery (ICA)for intervention.Neurology score was evaluated withLonga's.Brain water content (BWC)was detected with dry-humid weight method.Tetrazolium chloride (TTC)stain was used to count the volume percentage of the cerebralinfarction.Cell apoptosis was observed by TUNEL.And the alternation of aquaporin-4(AQP-4),Erg-1,STAT-3,GFAP,MMP-9,NSE,XIAP and Smac and their mRNA weredetermined through immunohistochemistry,double immunofluorescence labeling,immunoblotting and RT-PCR.Results①After the animal models were accomplished,all rats in the control groupshowed the neurology deficit symptom.Their BWC and the volume percentage of cerebralinfarction increased while the pretreatment and the treatment of NRG-1βobviouslyimproved the neurology deficit and decreased BWC and the infaction size.②NRG-1βpretreatment could attenuate the amount of cell apotosis,balanced the expression levels ofanti-apoptosis protein (XIAP)/pro-apoptosis protein (Smac),promote the presence of earlygrowth response gene-1 (Egr-1),actively suppress the development of inflammatoryresponse after ischemia cerebral damage.There were significant differences compared withthat in the control group (P＜0.05).③The administration of NRG-1βwithin 24 h aftercerebral ischemia could decrease the number of cell apoptosis in brain tissue and inhibit theinflammatory response,especially within 1.0 h,suggesting that the perfect therapeutic timewindow was at ischemic 1.0 h after MCAO.Its neuro-protective effects kept at least 24 h after the administration.④In the control group,ischemia and reperfusion could induceneurocyte apoptosis,reduce the expression levels of anti-apoptosis protein XIAP,andelevated the presence of pro-apoptosis protein Smac.NRG-1βtreatment significantlyincreased the anti-apoptosis and decreased the pro-apoptosis protein expressions in giventime after MCAO.⑤With the duration of brain ischemia,the increased expressions ofAQP-4,STAT-3,GFAP,MMP-9 and NSE proteins were shown in brain tissues to someextent;NRG-1βinjection could elevate AQP-4,STAT-3,GFAP and NSE and decreaseMMP-9 expression levels in some certain periods.Conclusion①NRG-1βpretreatment can stimulate the protective tolerance and efficientlykeep brain tissue from the second ischemic damage;②NRG-1βsignificantly attenueatesthe degree of brain damage,plays an active neuro-protective effects inischemia-reperfusion rats,which kept at least 24 h after the administration.The bestadministration time may be ischemic 1.0 h.③The neuroprotective effect of NRG-1βmay be achieved through activating early response gene,combining with its specialreceptors,inhibiting different links in the apoptosis pathway,reducing the development ofinflammatory response after cerebral ischemia and reperfusion,promoting the gliocyteproliferation and improving the survival environment of neurons.④As a newneuroprotective regent,NRG-1βis potent to apply for the clinical treatment of ischemicstroke.