ABSTRACT
OBJECTIVE: The endoplasmic reticulum (ER) -resident caspase-12 was identified as a mediator of Aß neurotoxicity. Recent evidence indicates that mitochondrial ATP-sensitive potassium (KATP) channel openers mediate their neuroprotective role by adjusting ER stress pathways, but the molecular details remain largely unknown and have been investigated. MATERIALS AND METHODS: In this study, the protein expression levels of calreticulin (CRT) and caspase-12 activation and phosphorylated p38 MAPK were observed by immunoblotting in cultured PC12 cells from different groups: treatment with Aß25-35 (group Aß25-35), treatment with diazoxide (group diazoxide), pretreatment with diazoxide and then exposure to Aß25-35 (group diazoxide + Aß25-35), pretreatment with p38 MAPK inhibitor SB 203580 and then exposure to diazoxide and Aß25-35 (group SB 203580 + diazoxide + Aß25-35), and the control (group control). RESULTS: In response to the treatment with Aß25-35 (10 µM) for 24 h, the protein expression levels of CRT and caspase-12 activation were increased and phosphorylated p38 MAPK was decreased significantly. Diazoxide reduced CRT overexpression and caspase-12 activation and increased the up-regulation of phosphorylated p38 MAPK. When SB 203580 was presented before exposure to diazoxide and Aß25-35, CRT expression was markedly suppressed, and the inhibition effect of diazoxide on caspase-12 activation was almost eliminated. CONCLUSIONS: We showed that diazoxide induced ERS-related neuroprotection mediated by p38 MAPK against Aß25-35 insults. From the clinical point of view, these results are of considerable importance for the understanding of AD pathogenesis. However, further studies are required to explore more detailed mechanisms of the observed effects.
