Inhibition Of MAPK Signaling Pathway And Tea Polyphenols Regulate Brain Of Rat Induced Cardiac Arrest Cardiopulmonary Resuscitation

Objectives:Cardiac arrest(CA)causes hippocampal neuronal and cortical neuronal death that frequently leads to severe loss of memory function in survivors.The clinical and experimental post cardiac arrest treatment has not reached therapeutic success.The activation of reactive oxygen species(ROS)and Mitogen-activated protein kinase(MAPK)are involved in development of pathological brain injury after ischemia in animal model.Antioxidant and inhibitors of MAPK are identified as an approach to alleviate cerebral ischemic/reperfusion(I/R)injury.Thus,the present thesis explored the neuroprotective functions of tea polyphenols(TP)and MAPK(ERK1/2,JNK,and p38)inhibitors in cerebral ischemia reperfusion of rats subjected to cardiac arrest(CA)/cardiopulmonary resuscitation(CPR).Method: Experimental rats were divided randomly into 6 groups: sham,CA,SP,PD,SKF,and TP.The rats except sham group were subjected to CA for 5 min followed by CPR operation.Once spontaneous circulation restored,saline and PD98059(10mg/kg),SP600125(6mg/kg),and SKF86002(2.5mg/kg),TP(10mg/kg)was injected in CA,PD,SP,SKF and TP groups respectively.The survival time and neurologic deficit scores(NDS)were observed,the following indices of brain tissue were evaluated: ROS,p-JNK/JNK,p ERK1/2/ERK1/2,pp38/p38,caspase-3,Bax,Bcl-2 TUNEL-positive cells and double fluorescent staining of p-JNK/TUNEL,p-ERK1/2/TUNEL and p-p38/TUNEL.Results:1.Compared to sham group,there were significant increased ROS and p-JNK,p-ERK,p-p38 in hippocampus of CA rat induced CA/CPR of reperfusion(p<0.05).2.PD treatment significantly reduced apoptotic neurons and improved the survival rates,NDS as compred to CA group(p<0.05).Moreover,PD markedly down-regulated the ROS,MDA,p-ERK,caspase-3,Bax and up-regulated SOD,Bcl-2 levels(p<0.05).Double staining pERK/TUNEL in choroid plexus and cortex showed that cells death are dependent on ERK activation.3.SP treatment significantly improved the survival rates,NDS and protects hippocampal neuron cells(p<0.05).Moreover,SP markedly downregulated the ROS,p-JNK,caspase-3,Bax and up-regulated Bcl-2 levels(p<0.05).4.Treatment with SKF induced increase ROS and decrease survival rate,NDS and the CA1 of hippocampus injury(p<0.05)as compared to CA group.Treatment with SP or PD reduced markedly ROS,increase survival rate and NDS(p<0.05).The results indicated that activation JNK and ERK may be involved in hippocampal neuronal cell death while activation of p38 may be involved in hippocampal neuroprotection.Moreover,we explored the mechanisms underlining ischemic tolerance effects of p38 may be associated with the suppression of ROS JNK-ERK pathways activation through the regulation of the apoptotic protein,as evidenced by a decrease caspase-3,Bax(p<0.05)and an increase Bcl-2(p<0.05)in rat subjected to CA/CPR.5.Compared to CA group,treatment with TP significantly reduced percentage of apoptosis,down-regulated caspase-3,Bax and up-regulated Bcl-2 in the cerebral cortex(p<0.05).Moreover,TP treatment suppressed JNK phosphorylation and double staining p-JNK/TUNEL.The results revealed that the neuroprotective effects of TP were associated with the inhibition of JNK pathway.Conclusions:The findings in present study demonstrated over generation of ROS may induced that activation JNK and ERK and p38 pathway in brain of rat subjected CA/CPR.The activation of p38 may be involved in neuronal cell survival while activation of ERK and JNK pathways may be involved in neuronal death.The mechanisms underlining ischemic tolerance effects of p38 pathway may be associated with the suppression of ROS,JNK and ERK pathways by the regulation of the apoptotic protein,such as caspase-3,Bax,and Bcl-2 in rat subjected to CA/CPR.The neuroprotective effects of TP are associated with the inhibition of JNK pathway.