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.
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