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

<jats:title>Abstract</jats:title><jats:p>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 <jats:styled-content style="fixed-case">DNA</jats:styled-content> 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 <jats:italic>N‐tert</jats:italic>‐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 <jats:italic>N‐tert</jats:italic>‐butyl‐α‐phenylnitrone, which reduced infarct volume and impaired neurological deficiency after cerebral ischemia and reperfusion in mice. Small interfering <jats:styled-content style="fixed-case">RNA</jats:styled-content> 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.</jats:p>