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

Authors

  • Jiwon Yang,

    1. Department of Pharmacology, College of Pharmacy, Sookmyung Women's University, Seoul, Republic of Korea
    Search for more papers by this author
  • Hye-na Ahn,

    1. Department of Pharmacology, College of Pharmacy, Sookmyung Women's University, Seoul, Republic of Korea
    Search for more papers by this author
  • Minsun Chang,

    1. Department of Medical and Pharmaceutical Science, College of Science, Sookmyung Women's University, Seoul, Republic of Korea
    Search for more papers by this author
  • Purnima Narasimhan,

    1. Department of Neurosurgery, Department of Neurology and Neurological Sciences, and Program in Neurosciences, Stanford University School of Medicine, Stanford, California, USA
    Search for more papers by this author
  • Pak H. Chan,

    1. Department of Neurosurgery, Department of Neurology and Neurological Sciences, and Program in Neurosciences, Stanford University School of Medicine, Stanford, California, USA
    Search for more papers by this author
  • Yun Seon Song

    Corresponding author
    1. Department of Neurosurgery, Department of Neurology and Neurological Sciences, and Program in Neurosciences, Stanford University School of Medicine, Stanford, California, USA
    • Department of Pharmacology, College of Pharmacy, Sookmyung Women's University, Seoul, Republic of Korea
    Search for more papers by this author

Address correspondence and reprint requests to Dr. Y. S. Song, College of Pharmacy, Sookmyung Women's University, Chungpa-ro 47 gil 100, Yongsan-ku, Seoul, 140-742, Korea. E-mail: yssong@sookmyung.ac.kr

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.

Ancillary