Protective effects of diazoxide against Aβ25-35-induced PC12 cell apoptosis due to prevention of endoplasmic reticulum stress

Accumulated amyloid-beta (A beta) is a well-known cause of neuronal apoptosis in Alzheimer's disease and exerts its action partly by inducing mitochondrial dysfunction. Previous studies have suggested a neuroprotective role for mitochondrial ATP-sensitive potassium (K-ATP) channel openers against A beta damages, but the molecular details were unclear. Recent evidence indicates that endoplasmic reticulum (ER) stress also plays an important role in the process of cell apoptosis. It remains to be determined whether K-ATP channel openers mediate their potential neuroprotective role by inhibiting ER stress pathways. The mRNA and protein expression levels of caspase-12, an ER-specific caspase, were observed. Here we showed that in response to the treatment with A beta(25-35) (10 mu M) for 24 h the mRNA and protein expression levels of caspase-12 were significantly upregulated; however, this change could be partly reversed by pretreatment with diazoxide (1 mM) for 1 h. This effect was negated by 5-hydroxydecanoate, a selective mitochondrial K-ATP channel blocker. Our results indicate that the cytoprotective efficacy of diazoxide under A beta(25-35)-induced insults is mediated, at least in part, by inhibition of ER stress. Demonstration of the neuroprotective action of diazoxide provides additional insights into the pathogenic mechanisms of A beta(25-35) toxicity and defines possible molecular targets for therapeutic intervention. NeuroReport 23:493-497 (C) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.