title: Protective effects of diazoxide against Aβ₂₅₋₃₅-induced PC12 cell apoptosis due to prevention of endoplasmic reticulum stress.
abstract: Accumulated amyloid-β (Aβ) 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 (KATP) channel openers against Aβ 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 KATP 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 Aβ₂₅₋₃₅ (10 μM) 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 KATP channel blocker. Our results indicate that the cytoprotective efficacy of diazoxide under Aβ₂₅₋₃₅-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 Aβ₂₅₋₃₅ toxicity and defines possible molecular targets for therapeutic intervention.
authors.affiliation: Department of Neurology, Yantaishan Hospital, Yantai City bDepartment of Neurology, Yuhuangding Hospital Affiliated to Qingdao Medical University, Yantai City, Shandong 264000, People's Republic of China.
authors.forename: Min
authors.initials: M
authors.lastname: Kong
authors.forename: Maowen
authors.initials: M
authors.lastname: Ba
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053454:Caspase 12 / Q000235:genetics / Q000378:metabolism; D003981:Diazoxide / Q000494:pharmacology*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016716:PC12 Cells; D010446:Peptide Fragments / Q000633:toxicity*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats
chemical_list: D016229:Amyloid beta-Peptides; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D012333:RNA, Messenger; C074636:amyloid beta-protein (25-35); D053454:Caspase 12; D003981:Diazoxide