Here we evaluated the effect of yonkenafil,a novel phosphodiesterase type 5 (PDE5) inhibitor, on ischemic injury and its possible mechanism of action.Male Sprague-Dawley rats were exposed to transient middle cerebral artery occlusion and treated with yonkenafil by intravenous or intraperitoneal injection 2 h later.Behavioral tests were carried out on day 1 or day 7 after reperfusion,while cerebral infarction, edema, Nissl staining, FluoroJade B staining and electron microscopy assays were carried out 24 h post-stroke.Regulation of classical apoptosis factors such as hsp70, apaf-1, caspase-9 and caspase-3 were detected by immunoblotting.Levels of cGMP-dependent Nogo-66 receptor (Nogo-R) pathway components, brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (TrkB) and nerve growth factor (NGF)/tropomyosin-related kinase A (TrkA) were also measured.Significant reductions of cerebral infarction and edema were observed when yonkenafil was administered within 4 h after ischemia onset.Meanwhile, this protection was associated with an ameliorative neurological function and was sustained for at least 7 d.Additionally, the range of penumbra was enlarged by yonkenafil, and the ischemic cell apoptosis and the loss of neurons were reduced, besides the contribution to modulating the expression of proteins in the Nogo-R pathway.Moreover, yonkenafil protected the structure of synapses and mediated the expression of synaptophysin and neurotrophic factors.In conclusion,these findings demonstrated that yonkenafil exerts neuroprotective effects in transient focal ischemia, which may involve an integrated process of neuronal networks.