Objective:To study the effects of mixed-lineage kinase 3 (MLK3) signaling pathway on neuron from hippocampal CA3 region in epilepsy rats and ischemia rats. Methods:Seizure models and cerebral ischemia models were induced by kainic acid (KA) and four-vessel occlusion in SD rats,respectively. Immunoblotting was performed to examine the activation of MLK3 and c-Jun N-terminal kinase (JNK) at different times after KA injection and ischemia-reperfusion (I/R) in hippocampal CA3 regions,respectively. The neuronal survival in hippocampal CA3 regions was observed by cresyl violet staining both in epilepsy rats and ischemia rats. Results:The phosphorylation of MLK3 and JNK in cytoplasm increased rapidly at 6 h after KA injection than those in the saline group,and still was in higher level at 1 d in hippocampal CA3 region (P < 0.05). Total protein expression of MLK3 and JNK showed no significant change. However,the expression of p-MLK3 and p-JNK showed no obvious changes at different time after reperfusion in hippocampal CA3 region. Furthermore,a large number of neurons were loss in hippocampal CA3 region at 7 d after KA injection. Correspondingly,no obvious neuronal damages were found in hippocampal CA3 regions at 7 d after reperfusion. Conclusion:MLK3/JNK signaling pathway plays an important role in neuronal cells death in hippocampal CA3 region in epilepsy rats,however,MLK3/JNK pathway does not mediate the neuronal survival in hippocampal CA3 region in ischemia rats.