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(Stroke. 2001;32:1906.)
© 2001 American Heart Association, Inc.

Original Contributions

Ebselen Reduces Cytochrome c Release From Mitochondria and Subsequent DNA Fragmentation After Transient Focal Cerebral Ischemia in Mice

Shobu Namura, MD, PhD; Izumi Nagata, MD, PhD; Shinya Takami, MS; Hiroyuki Masayasu, PhD Haruhiko Kikuchi, MD, PhD

From Stroke and Brain Protection Laboratory, Research Institute (S.N., S.T.), and Department of Neurosurgery (S.N., I.N., H.K.), National Cardiovascular Center, Osaka, and Daiichi Pharmaceutical Company Ltd, Tokyo (H.M.), Japan.

Reprint requests to Dr Shobu Namura, Stroke and Brain Protection Laboratory, National Cardiovascular Center, Suita, Osaka 565-8565, Japan. E-mail namura{at}ri.ncvc.go.jp

Background and Purpose—— The seleno-organic compound ebselen has both antioxidant and anti-inflammatory properties. Although ebselen has been shown to protect the brain against stroke, it is unclear how ebselen provides neuroprotection. In the present study the authors examined whether ebselen inhibits neuronal apoptosis resulting from transient focal cerebral ischemia in mice. The cytochrome c release and DNA fragmentation, both of which are biochemical markers of apoptosis, were compared between vehicle- and ebselen-treated mice.

Methods—— Cerebral ischemia was induced by transient middle cerebral artery occlusion for 30 minutes in ICR mice under halothane anesthesia. Ebselen (10 mg/kg) was given orally twice, 30 minutes before ischemia and 12 hours after reperfusion. By Western blot analysis, we examined release of mitochondrial cytochrome c. To evaluate brain damage, the brain sections were treated for terminal deoxynucleotidyl transferase–mediated DNA nick-end labeling (TUNEL) and Nissl staining. Prolonged neuroprotective efficacy of ebselen was determined by counting neuronal nuclei (NeuN) immunopositive cells at 21 days after ischemia.

Results—— Cytochrome c release was detected in the ischemic hemisphere at 3 to 24 hours after ischemia. Ebselen treatment diminished the cytochrome c release at 12 and 24 hours. In addition, ebselen decreased both DNA fragmentation determined by TUNEL and brain damage volume at 3 days after ischemia. Furthermore, ebselen increased the number of NeuN immunopositive cells at 21 days after ischemia.

Conclusions—— These results indicate that ebselen attenuates ischemic neuronal apoptosis by inhibiting cytochrome c release. Ebselen may be a potential compound in stroke therapy.

Key Words: apoptosis • cerebral ischemia, focal • neuroprotection • oxidative stress • mice

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