Objective Hydrogen sulfide (H2S) has been classified as a third novel gasotransmitter signaling molecule following nitric oxide and carbon monoxide.Accumulating evidence has shown that H2S produces physiological and pathophysiological functions in many organs and systems.The present study is designed to address the hypothesis that exogenous H2S could improve rat cognitive deficits induced by brain ischemia, and to explore the corresponding mechanism.Methods Rats were subjected to bilateral common carotid artery permanent occlusion for 15 days, and then spatial leaming and memory was examined by Morris water maze (MWM) test.Rats were administered with sodium hydrosulfide (NaHS, as an H2S donor, 5.6 mg/kg/day) intraperitoneally.Hippocampal long-term potentiation (LTP) from Schaffer collaterals to CA1 region was recorded.The morphology of neurons in CA1 region of hippocampus was determined by hematoxylin and eosin staining.The H2S content in hippocampus was evaluated.In addition, growth-associated protein-43 (GAP-43) and Tumor necrosis factor-alpha (TNF-α) expression in CA1 region of each rat was analyzed by immunohistochemical staining.Results Exogenous H2S significantly improved spatial cognition deficits induced by brain ischemia.MWM test showed the escape latencies were prolonged significantly post brain ischemia (P < 0.001),whereas NaHS treatment could shorten the prolonged escape latencies (P < 0.01).Meanwhile, quadrant dwell time was increased after NaHS treatment (P < 0.05).The H2S level in hippocampus of the rats endured NaHS treatment post ischemia was higher than that of ischemia rats (P < 0.001).In vivo LTP data showed that exogenous H2S could enhance the synaptic plasticity in hippocampus neurons in ischemic rats.Exogenous H2S could inhibit the edema around pyramidal neurons and the nuclear shrink induced by ischemia, promote the expression of GAP-43 and TNF-α in the CA1 region of hippocampus post ischemia.Conclusion Exogenous H2S has protective effects on neurons of hippocampus in brain ischemic rats, and it improves rat cognitive deficits caused by brain ischemia.The improving mechanisms are correlated with the function of H2S to facilitate synaptic plasticity post brain ischemia, promote axonal regeneration and sprouting in CA1 region of hippocampus, inhibit the inflammation induced by ischemia.It suggests a clinical importance and therapeutic potential of H2S in the treatment of brain ischemia.