Expression of bcl-2 from a defective herpes simplex virus-1 vector limits neuronal death in focal cerebral ischemia.
OBJECTIVE
A process resembling programmed cell death appears to contribute to postischemic neuronal loss in several models of stroke. Because the expression of the bcl-2 gene has been shown to rescue neurons from programmed cell death due to other causes, we determined whether it would be similarly neuroprotective in stroke.


METHODS
Replication of defective herpes viral vectors that transduce bcl-2 (HSVbcl2) or Escherichia coli lacZ (HSVlac) were injected into two sites in the rat cerebral cortex 24 hours before induction of neocortical focal ischemia by tandem permanent occlusion of the right middle cerebral artery and ipsilateral common carotid artery. Local ischemic damage was determined 24 hours after occlusion by staining with 2% 2,3,5-triphenyltetrazolium chloride.


RESULTS
Expression of bcl-2 in cerebral cortex was confirmed by immunohistochemistry in animals injected with the HSVbcl2 expression vector. Viable tissue was significantly increased at the injection sites in HSVbcl2- but not HSVlac-injected animals. The protection observed in the HSVbcl2 animals was localized to the injection sites.


CONCLUSIONS
These data indicate that bcl-2 expression protects neurons in vivo from ischemic injury and suggest the feasibility of gene therapy for stroke and perhaps other neurological diseases in which programmed cell death is involved.
Linnik
M D
MD
Department of Neurosurgery, University of Cincinnati College of Medicine, Marion Merrell Dow Research Institute, Ohio, USA.
Zahos
P
P
Geschwind
M D
MD
Federoff
H J
HJ
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D002540:Cerebral Cortex / Q000378:metabolism / Q000821:virology; D004926:Escherichia coli; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015967:Gene Expression Regulation, Viral; D005822:Genetic Vectors; D018259:Herpesvirus 1, Human / Q000235:genetics*; D002546:Ischemic Attack, Transient / Q000235:genetics / Q000473:pathology* / Q000821:virology; D009474:Neurons / Q000473:pathology*; D018696:Neuroprotective Agents; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D011519:Proto-Oncogenes / Q000235:genetics*; D051381:Rats; D011918:Rats, Inbred SHR; D013194:Staining and Labeling; D013778:Tetrazolium Salts
D018696:Neuroprotective Agents; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D013778:Tetrazolium Salts; C009591:triphenyltetrazolium; D011505:Protein-Tyrosine Kinases; D019204:GTP-Binding Proteins