title: Imipramine protects mouse hippocampus against tunicamycin-induced cell death.
abstract: Endoplasmic reticulum (ER) stress is implicated in various diseases. Recently, some reports have suggested that the sigma-1 receptor may play a role in ER stress, and many antidepressants have a high affinity for the sigma-1 receptor. In the present study, we focused on imipramine, a widely used antidepressant, and investigated whether it might protect against the neuronal cell death induced by tunicamycin, an ER stress inducer. In mouse cultured hippocampal HT22 cells, imipramine inhibited cell death and caspase-3 activation induced by tunicamycin, although it did not alter the elevated expressions of 78 kDa glucose-regulated protein (GRP78) and C/EBP-homologous protein (CHOP). Interestingly, in such cells application of imipramine normalized the expression of the sigma-1 receptor, which was decreased by treatment with tunicamycin alone. Additionally, NE-100, a selective sigma-1 receptor antagonist, abolished the protective effect of imipramine against such tunicamycin-induced cell death. Imipramine inhibited the reduction of mitochondrial membrane potential induced by tunicamycin, and NE-100 blocked this modulating effect of imipramine. Furthermore, in anesthetized mice intracerebroventricular administration of tunicamycin decreased the number of neuronal cells in the hippocampus, particularly in the CA1 and dentate gyrus (DG) areas, and 7 days' imipramine treatment (10mg/kg/day; i.p.) significantly suppressed these reductions in CA1 and DG. These findings suggest that imipramine protects against ER stress-induced hippocampal neuronal cell death both in vitro and in vivo. Such protection may be partly due to the sigma-1 receptor.
authors.affiliation: Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Ono
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Shimazawa
authors.forename: Mitsue
authors.initials: M
authors.lastname: Ishisaka
authors.forename: Atsushi
authors.initials: A
authors.lastname: Oyagi
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Tsuruma
authors.forename: Hideaki
authors.initials: H
authors.lastname: Hara
mesh_terms: D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007099:Imipramine / Q000494:pharmacology*; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D017480:Receptors, sigma / Q000378:metabolism; D014415:Tunicamycin; D000097605:Sigma-1 Receptor
chemical_list: D000929:Antidepressive Agents, Tricyclic; D053148:Caspase 3; D000091342:Endoplasmic Reticulum Chaperone BiP; D007099:Imipramine; D018696:Neuroprotective Agents; D017480:Receptors, sigma; D014415:Tunicamycin; D000097605:Sigma-1 Receptor; C000717248:Hspa5 protein, mouse