title: Ebselen reduces cytochrome c release from mitochondria and subsequent DNA fragmentation after transient focal cerebral ischemia in mice.
abstract: OBJECTIVE
  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.
authors.affiliation: Stroke and Brain Protection Laboratory, Department of Neurosurgery, National Cardiovascular Center, Osaka, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Namura
authors.forename: I
authors.initials: I
authors.lastname: Nagata
authors.forename: S
authors.initials: S
authors.lastname: Takami
authors.forename: H
authors.initials: H
authors.lastname: Masayasu
authors.forename: H
authors.initials: H
authors.lastname: Kikuchi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001393:Azoles / Q000494:pharmacology*; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D003574:Cytochrome c Group / Q000378:metabolism*; D053938:DNA Fragmentation / Q000187:drug effects*; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D020287:In Situ Nick-End Labeling; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D054833:Isoindoles; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D016566:Organoselenium Compounds / Q000494:pharmacology*
chemical_list: D001393:Azoles; D003574:Cytochrome c Group; D054833:Isoindoles; D018696:Neuroprotective Agents; D016566:Organoselenium Compounds; C042986:ebselen; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases