Diazoxide pretreatment prevents Aβ1-42 induced oxidative stress in cholinergic neurons via alleviating NOX2 expression.
The aggregation and accumulation of amyloid-β (Aβ) plays a significant role in the pathogenesis of Alzheimer's disease. Aβ is known to increase free radical production in neuronal cells, leading to oxidative stress and cell death. Diazoxide (DZ), a highly selective drug capable of opening mitochondrial ATP-sensitive potassium channels, has neuroprotective effects against neuronal cell death. However, the mechanism through which DZ protects cholinergic neurons against Aβ-induced oxidative injury is still unclear. The present study was designed to investigate the effects of DZ pretreatment against Aβ1-42 induced oxidative damage and cytotoxicity. Through measures of DZ effects on Aβ1-42 induced cellular damage, reactive oxygen species (ROS) and MDA generation and expressions of gp91phox and p47phox in cholinergic neurons, new insights into the neuroprotective mechanisms can be derived. Aβ1-42 significantly decreased 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide levels and increased ROS and MDA production; all effects were attenuated by pretreatment with DZ or diphenyleneiodonium chloride (a NOX2 inhibitor). Pretreatment with DZ also attenuated the upregulation of NOX2 subunits (gp91phox and p47phox) induced by Aβ1-42. Since NOX2 is one of the main sources of free radicals, these results suggest that DZ can counteract Aβ1-42 induced oxidative stress and associated cell death by reducing the level of ROS and MDA, in part, by alleviating NOX2 expression.
Department of Neurology, Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, People's Republic of China.
Qingxi
Q
Fu
Naiyong
N
Gao
Jixu
J
Yu
Guozhao
G
Ma
Yifeng
Y
Du
Fumin
F
Wang
Quanping
Q
Su
Fengyuan
F
Che
D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000633:toxicity*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D059329:Cholinergic Neurons / Q000187:drug effects* / Q000201:enzymology; D003981:Diazoxide / Q000008:administration & dosage*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000633:toxicity*; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D016896:Treatment Outcome
D016229:Amyloid beta-Peptides; D008562:Membrane Glycoproteins; D018696:Neuroprotective Agents; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); C500593:Cybb protein, rat; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D003981:Diazoxide