The calcium sensitizers levosimendan and piperphentonamine hydrochloride (PPTA) are used as cardiovascular drugs for treatment of heart failure. Given that levosimendan has been reported to exhibit a neuroprotective profile in a model of traumatic brain injury, it was interesting to know whether PPTA, a new calcium sensitizer recently developed in China, exerts a similar effect. The objective of this study was to determine whether PPTA exhibited neuroprotective effects and whether these properties were associated with memory. Four-vessel occlusion (4-VO) was used to induce global cerebral ischemia/reperfusion injury in rats treated with or without PPTA (5, 10 mg/kg, i.p., 2 h after the onset of reperfusion and then once a day for 15 consecutive days). Memory was measured using the step-through passive avoidance test. Neurochemical changes were examined in rat PC12 cells treated with oxygen-glucose deprivation (OGD) for 4 h followed by reoxygenation (OGD-R) for 24 h, in the absence or presence of PPTA. In vehicle-treated animals, 4-VO for 10 min produced memory deficits, as demonstrated by decreased retention in step-through passive avoidance, and massive neuron loss in the hippocampal CA1 subregion. These effects were attenuated by PPTA. The results were consistent with those observed in PC12 cells. PPTA treatment increased cell viability, as indicated by MTT assay, inhibited apoptosis, and decreased extracellular lactate dehydrogenase levels in Na(2)S(2)O(4)-treated PC12 cells. These results provide novel demonstration for the ability of PPTA to attenuate cerebral ischemia-induced memory deficits via neuroprotection in the hippocampus. The neuroprotective effect of PPTA appears to be associated with its anti-apoptotic activity. PPTA has the therapeutic potential for ischemic stroke.