title: Subregion-specific vulnerability to endoplasmic reticulum stress-induced neurotoxicity in rat hippocampal neurons.
abstract: It is well known that in certain disease states, including ischemia and Alzheimer's disease, neurodegeneration occurs in the hippocampus and that vulnerability to neuronal death is area dependent. The present study investigated the mechanism of area-dependent vulnerability to neuronal death under endoplasmic reticulum stress conditions induced by tunicamycin (TM), using rat organotypic hippocampal cultures (OHC) and hippocampal slices. Analysis of propidium iodide uptake showed that TM-induced neuronal death in a concentration-dependent manner (20-80 microg/mL) and that the rank order of vulnerability among hippocampal subregions was dentate gyrus (DG)>CA1>CA3. Results of immunohistochemistry using hippocampal slices also showed that procaspase-12-positive cells in area CA3 were significantly fewer than those in area CA1 and the DG. Moreover, procurement of neurons in areas CA1, CA3 and the DG by laser microdissection, followed by Western blot analysis, also revealed that the level of procaspase-12 in area CA3 was significantly lower than those in area CA1 and the DG. Pretreatment with z-ATAD-fmk, a cell-permeable caspase-12-selective inhibitor significantly attenuated the TM-induced increase of PI fluorescence in the CA1 and DG subregion but not in area CA3. These results suggest that TM elicits subregion-specific neuronal toxicity in OHC and that the vulnerability to TM-induced toxicity is at least partly dependent on the expression level of endogenous procaspase-12 in each area of the hippocampus.
authors.affiliation: Research Unit of Pharmacology, Department of Clinical Pharmacy, College of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi-shi, Chiba 274-8555, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kosuge
authors.forename: Toru
authors.initials: T
authors.lastname: Imai
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Kawaguchi
authors.forename: Tetsuroh
authors.initials: T
authors.lastname: Kihara
authors.forename: Kumiko
authors.initials: K
authors.lastname: Ishige
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Ito
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D053454:Caspase 12 / Q000378:metabolism*; D018891:Dentate Gyrus / Q000378:metabolism / Q000503:physiopathology; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D009410:Nerve Degeneration / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009498:Neurotoxins / Q000633:toxicity; D009924:Organ Culture Techniques; D018384:Oxidative Stress / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D014415:Tunicamycin / Q000633:toxicity
chemical_list: D004791:Enzyme Inhibitors; D009498:Neurotoxins; D014415:Tunicamycin; D053454:Caspase 12