Objective To investigate the effect of 6-gingerol treatment on cognitive behavior after hypoxic-ischemic brain injury (HIE) in neonatal mice, and to explore the protective mechanism of 6- gingerol on HIE brain injury in neonatal mice by observing the effects on neuronal survival and neural stem cell proliferation.   Methods The right common carotid artery was ligated in Kunming mice（78）on the 7th day after birth and HIE model was established after 90 minutes of hypoxic treatment.  6-gingerol was injected intraperitoneally. The cognitive behavior was detected by Morris water maze test; 2,3,5-triphenyl tetrazolium chloride(TTC) staining was used to observe the changes of brain injury; The changes of synaptic structure and number were obseved by transmission electron microscopy; HE staining, Nissl staining and dihydroethidium(DHE) staining were used to observe the pathomorphological changes of hippocampus in each group; The proliferation of neural stem cells and the expression of related transcription factors were detected by immunofluorescence and Real-time PCR; The changes of Akt signal pathway were detected by Western blotting.   Results 6-gingerol treatment could improve the long-term learning and memory ability, reduce the brain injury and brain edema of neonatal mice after HIE, and improve synaptic plasticity of mice after HIE. In the 6-gingerol treatment group, the disorder of hippocampal cells in the diseased side of HIE was improved, the number of necrotic cells decreased, the proliferation ability of hippocampal neural stem cells and the expression levels of nestin and sex determining region box transcription factor 2(Sox2) related transcription factors increased significantly, and the level of phosphorylated Akt(p-Akt) increased.     Conclusion It  is found that 6-gingerol can improve the learning and memory ability of HIE mice in adulthood and reduce brain tissue injury after HIE. 6-gingerol may play a role in inhibiting the production of reactive oxygen species(ROS), reducing neuronal injury and upregulating the expression of Akt signal pathway, promoting the proliferation of hippocampal neural stem cells, so as to provide potential drugs for the treatment of neonatal HIE.

6-gingerol, Hypoxic-ischemic brain injury, Neural stem cell, Neuron, Cognitive behavior, Transmission electron microscopy, Neonatal mouse