OBJECTIVE: To investigate the effect of adenosine A2A receptor knockout (A(2A)RKO) on relationship between continuous activation of phospho-c-Jun N-terminal kinase (P-JNK) and expression of nerve cell apoptosis in hippocampus CA1 domain of newborn mice after hypoxia/ischemia brain damage(HIBD) and its potential mechanism. METHODS: A(2A)RKO mice and adenosine A2A receptor wildtype (A(2A)RWT) littermates (n = 80) were divided into Sham operation group (S) and model group (M), 1, 3 and 7 day after HIBD, totally 8 groups. HIBD was developed with 7 day-old neonatal mice according classical Rice-Vannucci method. It was tested the effect of A(2A)RKO on short-term neurofunctional outcomes consisted of three developmental reflexes (righting, geotaxis and cliff aversion), the changes of brain pathology with hematoxylin-eosin (HE) staining and Nissl staining, the expressions of nerve cell apoptosis with terminal deoxynucleotidyl transferase mediated dUTP-biotin nick-end labeling(TUNEL) staining and P-JNK were observed by immunohistochemistry. RESULTS: The neurological behavior injuries and brain histopathological damages and nerve apoptosis cells were aggravated in A(2A)RKO newborn mice after HIBD. The positive expressions of P-JNK were significantly higher in the ischemic hippocampus CA1 domain after HIBD than ones in group S respectively (P < 0.01), reaching to peak at 1 day and then began gradually decreasing. P-JNK expression in model knockout(MKO) at 1, 3 and 7 day increased greatly compared to those in the previous time point of corresponding model wildtype (MWT) (P < 0.01, P < 0.05, P > 0.05); there was a positive correlation between the expressions of P-JNK and nerve cell apoptosis after HIBD in newborn mice(r = 0.837, P < 0.01). CONCLUSION: Early continuous activation of P-JNK might be involved in the aggravated nerve apoptosis cells and brain damage induced by A(2A) RKO newborn mice after HIBD.