Objective To study the role of heme oxygenase-1(HO-1) and endogenous carbon monoxide(CO) on hypoxia-ischemic brain damage(HIBD) in newborn rats and therapeutic effect of the Znpp on HIBD.Methods Models of HIBD in newborn rats were established. Znpp was injected into the abdominal cavity of rats in Znpp group before hypoxic-ischemia. HO-1 activity,cGMP level in the brain and CO level in the blood were determined respectively at 1,4,12 and 24 h after hypoxic-ischemia by spectrophotometry etc. Results HO-1 activity、CO and cGMP level of HI group were significant higher than those of control groups at 1,4,12 h(P0.01);In HI,neurons were damaged severely. Znpp could effectively antagonize the pathological changes mentioned above. Conclusions In HIBD,the increased HO-1 activity resulted in increase of endogenous CO that can enhance cGMP;Znpp may protect nerve cells from damage by preventing HO-1 activity resulted in a decrease of endogenous CO. HO-CO-cGMP system may play an important role in the pathogenesis of HIBD.