title: Protective action of mithramycin against neurodegeneration and impairment of synaptic plasticity in the hippocampal CA1 area after transient global ischemia.
abstract: Mithramycin A (MTM) is an antibiotic used for the treatment of hypercalcemia and several types of cancer. We have reported previously that MTM protects against endoplasmic reticulum (ER) stress-induced neuronal death in organotypic hippocampal slice cultures. In the present study, the neuroprotective effect of MTM against ischemia/reperfusion-induced neuronal injury was evaluated in the hippocampus in mice. Neuronal damage was apparent in area CA1 of the hippocampus after transient global ischemia/reperfusion. The expression of C/EBP homologous protein (CHOP), a key transcription factor for ER stress-induced neuronal death, showed a pronounced increase in area CA1 in these mice. Treatment of the mice with MTM significantly decreased both the number of neurons stained with Fluoro-Jade B and the level of CHOP expression in the hippocampus. MTM did not affect the increase of 78-kDa glucose-regulated protein induced by ischemia/reperfusion. MTM also restored the ischemia/reperfusion-induced impairment of long-term potentiation in the hippocampus, without any change in paired pulse facilitation. These results suggest that administration of MTM protects hippocampal neurons against injury induced by transient global ischemia/reperfusion through attenuation of ER stress-associated signals, and ameliorates neuronal injury induced by ischemia/reperfusion in the hippocampus.
authors.affiliation: Laboratory of Pharmacology, School of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi-shi, Chiba 274-8555, Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Osada
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kosuge
authors.forename: Sayuri
authors.initials: S
authors.lastname: Oguchi
authors.forename: Hiroko
authors.initials: H
authors.lastname: Miyagishi
authors.forename: Kumiko
authors.initials: K
authors.lastname: Ishige
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Ito
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000187:drug effects* / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D002546:Ischemic Attack, Transient / Q000378:metabolism*; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009473:Neuronal Plasticity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D008926:Plicamycin / Q000494:pharmacology*; D015427:Reperfusion Injury / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects*
chemical_list: D018696:Neuroprotective Agents; D008926:Plicamycin