Abstract: OBJECTIVE To evaluate the effect of hydrogen-rich saline on hippocampus PERK/eIF2α/ATF4 protein signaling pathways in mice after transient cerebral ischemia reperfusion injury. METHODS One hundred and fifty healthy male C57BL/6 mice were divided into 5 groups(n=30) using a random number table: control group, sham operation group, cerebral ischemia-reperfusion group, hydrogen-rich saline treatment group and normal saline treatment group. Neurobehavioral score was assessed at 12, 24 h of reperfusion. Then mice in each group were sacrificed, and the hippocampal tissues were obtained and the apoptosis index of CA1 in hippocampus were determined by TUNEL. The expression of PERK, eIF2α, ATF4, CHOP, caspase-3 protein and mRNA were determined by Western blotting and real-time polymerase chain reaction, respectively. RESULTS Compared with the control group and the sham operation group, the neurobehavioral score and apoptosis index of hippocampal CA1 region were increased, and the expression of PERK, eIF2α, ATF4, CHOP, caspase-3 and their mRNA were up-regulated in the cerebral ischemia-reperfusion group, hydrogen-rich saline treatment group and normal saline treatment group(all P<0.05). Compared with cerebral ischemia-reperfusion group and normal saline treatment group, the neurobehavioral score and apoptosis index in hippocampus CA1 region were decreased and the expression of PERK, eIF2α, ATF4, CHOP, caspase-3 and their mRNA were down-regulated in the hydrogen-rich saline treatment group(all P<0.05). CONCLUSION Hydrogen-rich saline can improve transient cerebral ischemia reperfusion injury in mice, and its mechanism may be associated with inhibited activation of PERK/eIF2α/ATF4 signaling pathway.