Complement component 3 inhibition by an antioxidant is neuroprotective after cerebral ischemia and reperfusion in mice

• Published in: Journal of neurochemistry Vol. 124; no. 4; pp. 523 - 535
• Main Authors: Yang, Jiwon, Ahn, Hye‐na, Chang, Minsun, Narasimhan, Purnima, Chan, Pak H., Song, Yun Seon
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.02.2013
• Subjects: Animals; antioxidant; Brain; Brain - drug effects; Brain - metabolism; Brain - pathology; Brain Ischemia - blood; Brain Ischemia - complications; Brain Ischemia - drug therapy; Brain Ischemia - pathology; Cell Survival - drug effects; Cell Survival - genetics; Cells, Cultured; Cerebral Cortex - cytology; Complement C3 - genetics; Complement C3 - metabolism; complement component 3; Cyclic N-Oxides - therapeutic use; Cyclooxygenase 2 - metabolism; Disease Models, Animal; Down-Regulation - drug effects; Down-Regulation - genetics; Enzyme-Linked Immunosorbent Assay; focal cerebral ischemia; Glucose - deficiency; Hypoxia; Ischemia; L-Lactate Dehydrogenase - metabolism; Male; Mice; Mice, Transgenic; Nervous System Diseases - etiology; Nervous System Diseases - prevention & control; Neurochemistry; Neuroglia - drug effects; Neuroglia - metabolism; Neurons - drug effects; Neurons - metabolism; Neuroprotective Agents - therapeutic use; Oxidative stress; Oxidative Stress - drug effects; Oxidative Stress - genetics; Reactive Oxygen Species - metabolism; Reperfusion Injury - prevention & control; RNA, Messenger - metabolism; Stroke; Superoxide Dismutase - deficiency; Superoxide Dismutase - genetics; Superoxide Dismutase-1; Time Factors; Up-Regulation - drug effects; Up-Regulation - physiology
• ISSN: 0022-3042; 1471-4159; 1471-4159
• DOI: 10.1111/jnc.12111

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. Our result showed that complement component 3 (C3) activation was down‐regulated by antioxidant after cerebral ischemia, and was neuroprotective in mice model. Oxidative stress was highly related to C3activation after stroke, and C3 knock‐down reduced ROS in primary neurons after hypoxia. An antioxidant that is able to inhibit C3 may offer the new strategy for therapeutic approaches in stroke.