title: Complement component 3 inhibition by an antioxidant is neuroprotective after cerebral ischemia and reperfusion in mice.
abstract: Oxidative stress after stroke is associated with the inflammatory system activation in the brain. The complement cascade, especially the degradation products of complement component 3, is a key inflammatory mediator of cerebral ischemia. We have shown that pro-inflammatory complement component 3 is increased by oxidative stress after ischemic stroke in mice using DNA array. In this study, we investigated whether up-regulation of complement component 3 is directly related to oxidative stress after transient focal cerebral ischemia in mice and oxygen-glucose deprivation in brain cells. Persistent up-regulation of complement component 3 expression was reduced in copper/zinc-superoxide dismutase transgenic mice, and manganese-superoxide dismutase knock-out mice showed highly increased complement component 3 levels after transient focal cerebral ischemia. Antioxidant N-tert-butyl-α-phenylnitrone treatment suppressed complement component 3 expression after transient focal cerebral ischemia. Accumulation of complement component 3 in neurons and microglia was decreased by N-tert-butyl-α-phenylnitrone, which reduced infarct volume and impaired neurological deficiency after cerebral ischemia and reperfusion in mice. Small interfering RNA specific for complement component 3 transfection showed a significant increase in brain cells viability after oxygen-glucose deprivation. Our study suggests that the neuroprotective effect of antioxidants through complement component 3 suppression is a new strategy for potential therapeutic approaches in stroke.
authors.affiliation: Department of Pharmacology, College of Pharmacy, Sookmyung Women's University, Seoul, Republic of Korea.
authors.forename: Jiwon
authors.initials: J
authors.lastname: Yang
authors.forename: Hye-Na
authors.initials: HN
authors.lastname: Ahn
authors.forename: Minsun
authors.initials: M
authors.lastname: Chang
authors.forename: Purnima
authors.initials: P
authors.lastname: Narasimhan
authors.forename: Pak H
authors.initials: PH
authors.lastname: Chan
authors.forename: Yun Seon
authors.initials: YS
authors.lastname: Song
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D003176:Complement C3 / Q000235:genetics / Q000378:metabolism*; D003497:Cyclic N-Oxides / Q000627:therapeutic use*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D005947:Glucose / Q000172:deficiency; D000860:Hypoxia; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009422:Nervous System Diseases / Q000209:etiology / Q000517:prevention & control; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000517:prevention & control*; D013482:Superoxide Dismutase / Q000172:deficiency / Q000235:genetics; D000072105:Superoxide Dismutase-1; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*; D000099156:Superoxide Dismutase 2
chemical_list: D003176:Complement C3; D003497:Cyclic N-Oxides; D051546:Cyclooxygenase 2; D005947:Glucose; D007770:L-Lactate Dehydrogenase; D018696:Neuroprotective Agents; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D000099156:Superoxide Dismutase 2; C029217:phenyl-N-tert-butylnitrone; C000606291:Sod1 protein, mouse