title: A sigma-1 receptor antagonist (NE-100) prevents tunicamycin-induced cell death via GRP78 induction in hippocampal cells.
abstract: 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 (p50ATF6) and the 78-kDa glucose-regulated protein (GRP78). However, NE-100 did not impact the expression of phosphorylated eukaryotic initiation factor 2α (p-eIF2α) 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.
authors.affiliation: Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Ono
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Tanaka
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Tsuruma
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Shimazawa
authors.forename: Hideaki
authors.initials: H
authors.lastname: Hara
mesh_terms: D051702:Activating Transcription Factor 6 / Q000378:metabolism; D017398:Alternative Splicing / Q000187:drug effects; D000818:Animals; D000840:Anisoles / Q000494:pharmacology*; D015153:Blotting, Western; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D011437:Propylamines / Q000494:pharmacology*; D017480:Receptors, sigma / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051742:Transcription Factor CHOP / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014415:Tunicamycin / Q000494:pharmacology*; D000071717:X-Box Binding Protein 1; D000097605:Sigma-1 Receptor
chemical_list: D051702:Activating Transcription Factor 6; D000840:Anisoles; D004268:DNA-Binding Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2; D006360:Heat-Shock Proteins; D011437:Propylamines; D017480:Receptors, sigma; D000071701:Regulatory Factor X Transcription Factors; D051742:Transcription Factor CHOP; D014157:Transcription Factors; D014415:Tunicamycin; D000071717:X-Box Binding Protein 1; D000097605:Sigma-1 Receptor; C497112:Atf6 protein, mouse; C497250:Ddit3 protein, mouse; C000717248:Hspa5 protein, mouse; C000605544:Xbp1 protein, mouse; C083832:N,N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)ethylamine monohydrochloride