title: Bcl-2 overexpression protects against neuron loss within the ischemic margin following experimental stroke and inhibits cytochrome c translocation and caspase-3 activity.
abstract: Bcl-2 protects against both apoptotic and necrotic death induced by several cerebral insults. We and others have previously demonstrated that defective herpes simplex virus vectors expressing Bcl-2 protect against various insults in vitro and in vivo, including cerebral ischemia. Because the infarct margin may be a region that is most amenable to treatment, we first determined whether gene transfer to the infarct margin is possible using a focal ischemia model. Since ischemic injury with and without reperfusion may occur by different mechanisms, we also determined whether Bcl-2 protects against focal cerebral ischemic injury either with or without reperfusion in rats. Bax expression, cytochrome c translocation and activated caspase-3 expression were also assessed. Viral vectors overexpressing Bcl-2 were delivered to the infarct margin. Reperfusion resulted in larger infarcts than permanent occlusion. Bcl-2 overexpression significantly improved neuron survival in both ischemia models. Bcl-2 overexpression did not alter overall Bax expression, but inhibited cytosolic accumulation of cytochrome c and caspase-3 activation. Thus, we provide the first evidence that gene transfer to the infarct margin is feasible, that overexpression of Bcl-2 protects against damage to the infarct margin induced by ischemia with and without reperfusion, and that Bcl-2 overexpression using gene therapy attenuates apoptosis-related proteins. This suggests a potential therapeutic strategy for stroke.
authors.affiliation: Department of Neurosurgery, Stanford University School of Medicine, 300 Pasteur Drive R200, Stanford, CA 94305-5327, USA.
authors.forename: Heng
authors.initials: H
authors.lastname: Zhao
authors.forename: Midori A
authors.initials: MA
authors.lastname: Yenari
authors.forename: Danye
authors.initials: D
authors.lastname: Cheng
authors.forename: Robert M
authors.initials: RM
authors.lastname: Sapolsky
authors.forename: Gary K
authors.initials: GK
authors.lastname: Steinberg
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000209:etiology / Q000473:pathology / Q000628:therapy*; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D002452:Cell Count; D003574:Cytochrome c Group / Q000378:metabolism*; D004195:Disease Models, Animal; D004333:Drug Administration Routes; D005455:Fluorescent Antibody Technique; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000628:therapy; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology; D051381:Rats; D015424:Reperfusion; D020521:Stroke / Q000209:etiology / Q000473:pathology / Q000628:therapy*; D051028:bcl-2-Associated X Protein
chemical_list: C494828:Bax protein, rat; D061945:Caspase Inhibitors; D003574:Cytochrome c Group; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases