Endoplasmic reticulum (ER) stress is involved in various diseases such as ischemia, Alzheimer's disease, and Parkinson's disease. The widely used selective sigma-1 receptor antagonist, N, N-dipropyl-2[4-methoxy-3-(2-phenylethoxy)-phenyl]-ethylamine monohydrochloride (NE-100), has been shown to suppress ischemia-induced neuronal cell death in the murine hippocampus. In the present study, we investigated whether NE-100 might suppress neuronal cell death that is induced by ER stress in ischemic injury. These studies show that NE-100 protected the ER stress-induced cell death of murine hippocampal HT22 cells, but not the oxidative stress-induced cell death. This suggests that NE-100 may have a protective effect on the ER. However, another sigma-1 receptor antagonist (BD1047) did not suppress ER stress-induced cell death. In addition, NE-100 attenuated the upregulation of C/EBP homologous protein (CHOP) induced by ER stress and upregulated the expression of both the 50-kDa activating transcription factor 6 (p5OATF6) and the 78-kDa glucose-regulated protein (GRP78). However, NE-100 did not impact the expression of phosphorylated eukaryotic initiation factor 2 alpha (p-eIF2 alpha) nor splicing of X-box-binding protein 1(XBP-1). These findings suggest that NE-100 suppresses ER stress-induced cell death via CHOP expression by the upregulation of GRP78 through ATF6 pathway, independent sigma-1 receptor antagonist effect. (C) 2013 Elsevier Inc. All rights reserved.