To better understand the neuroprotective actions of agmatine in ischemic insults, its effects on astrocytes were investigated using an in vitro oxygen-glucose deprivation (OGD) model. After primary culture, cortical astrocytes were moved into a closed anaerobic chamber and incubated in glucose-free culture media. 4 h later, the cells were restored to normoxic conditions and supplied with glucose for 20 h. The ability of agmatine to rescue astrocytes from OGD only and OGD followed by restoration (OGD-R) was assessed. Cell viability was monitored with or without 100 muM agmatine, using the lactate dehydrogenase (LDH) assay and annexin V flow cytometric assay. For morphological analysis, Hoechst 33258 and propidium iodide double nuclear staining was performed. Expression and phosphorylation of nuclear factor-kappa B (NF-kappaB) family proteins were also investigated by immunoblotting. Results showed that astrocytes had decreased viability following OGD and OGD-R and that agmatine treatment increased cell viability and induced NF-kappaB translocation into the nucleus. Finally, our studies revealed that agmatine can rescue astrocytes from death caused by ischemic and/or ischemic-perfusion neuronal injuries in vitro. Our findings provide new insights that may lead to a novel therapeutic strategy to reduce these kinds of neuronal injuries.