Endoplasmic reticulum (ER)-stress is known to induce neuronal cell death and to play roles in neurodegenerative diseases. Phosphorylation of double stranded RNA-dependent protein kinase (PKR) has been demonstrated in brain tissues in patients with Alzheimer's, Parkinson's, and Huntington's diseases. Here, we examined the effect of a PKR inhibitor (an imidazolo-oxindole derivative that acts as an ATP-binding site-directed inhibitor of PKR) on the neuronal cell death induced by ER-stress in cultured human neuroblastoma cells (SH-SY5Y). Cell damage was induced by tunicamycin (an ER-stress inducer), and cell viability was measured by Hoechst 33342 and YO-PRO-1 double staining and by the resazurin-reduction test (to evaluate metabolic activity). Treatment with tunicamycin at 2 microg/ml for 24 h induced apoptotic cell death accompanied by nuclear condensation and/or fragmentation, and these cells were positive for YO-PRO-1 (early-phase apoptosis and necrosis indicator). Treatment with the PKR inhibitor at 0.1 or 0.3 microM led to a decrease in the number of apoptotic cells induced by tunicamycin. In the resazurin-reduction test, the PKR inhibitor (at 0.1 and 0.3 microM) concentration-dependently inhibited the tunicamycin-induced decrease in metabolic activity. On the other hand, treatment with the PKR inhibitor alone (at 0.3 microM) had no effect on cell morphology or viability (versus in normal control cells). These results indicate that inhibition of PKR activation may be neuroprotective against ER stress-induced cell damage.