title: T-817MA, a novel neurotrophic agent, improves sodium nitroprusside-induced mitochondrial dysfunction in cortical neurons.
abstract: 1-{3-[2-(1-Benzothiophen-5-yl)ethoxy]propyl}-3-azetidinol maleate (T-817MA), a novel neurotrophic agent, protects against amyloid-beta peptide- or hydrogen peroxide-induced neuronal death. The exact mechanism of the neuroprotection is not known. This study examines the effects of T-817MA on oxidative stress-induced cytotoxicity in primary rat cortical neurons. Treatment with the NO donor sodium nitoroprusside (SNP) at 300microM decreased cell viability and induced apoptotic cell death. SNP-induced neuronal toxicity was accompanied by a decrease in mitochondrial transmembrane potential without an increase in the expression of CHOP and GRP78 mRNAs, endoplasmic reticulum stress makers. T-817MA at 0.1 and 1microM attenuated the neurotoxicity in a dose-dependent way and the protective effect required pretreatment for more than 8h. T-817MA attenuated SNP-induced decrease in mitochondrial transmembrane potential. In addition, the agent reduced SNP-induced increase in mitochondrial reactive oxygen species (ROS) production. The effects of T-817MA on SNP-induced decrease in cell viability and SNP-induced increase in mitochondrial ROS production were blocked by cycloheximide. These results suggest that T-817MA improves SNP-induced mitochondrial dysfunction in cortical neurons in a newly synthesized protein-mediated mechanism and this effect contributes to its neuroprotective effect.
authors.affiliation: Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Fukushima
authors.forename: Masahiro
authors.initials: M
authors.lastname: Koide
authors.forename: Yukio
authors.initials: Y
authors.lastname: Ago
authors.forename: Akemichi
authors.initials: A
authors.lastname: Baba
authors.forename: Toshio
authors.initials: T
authors.lastname: Matsuda
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects* / Q000473:pathology; D017931:DNA Primers; D005260:Female; D008298:Maleates / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009599:Nitroprusside / Q000494:pharmacology*; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D013876:Thiophenes / Q000494:pharmacology*
chemical_list: C503102:1-(3-(2-(1-benzothiophen-5-yl) ethoxy) propyl)-3-azetidinol maleate; D017931:DNA Primers; D008298:Maleates; D018696:Neuroprotective Agents; D013876:Thiophenes; D009599:Nitroprusside