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Liposome-mediated transfer of the bcl-2 gene results in neuroprotection after in vivo transient focal cerebral ischemia in a animal model.

Authors :
Cao, Y.-J.
Shibata, T.
Rainov, N.C.
Source :
Gene Therapy. 3/15/2002, Vol. 9 Issue 6, p415. 5p.
Publication Year :
2002

Abstract

Acute cerebral ischemia causes hypoxic neuronal cell death by necrosis and apoptosis. Expression of anti-apoptotic transgenes in ischemic brain may provide a useful therapeutic strategy for alleviation of postischemic damage. The present study investigates liposome-mediated transfer of the human bcl-2 protein in a rat model of focal transient ischemia due to middle cerebral artery (MCA) occlusion. Two different types of plasmid vectors were used for bcl-2 expression: one driven by the constitutive cytomegalovirus promoter (pCMV) and another based on the hypoxiainducible human vascular endothelial growth factor promoter (pHRE). Cationic liposome/plasmid DNA complexes (lipoplexes) were injected directly into the cerebrospinal fluid (CSF) of rats immediately after MCA occlusion. The brains of treated and control animals were analyzed 48 h later. Infarct volumes and numbers of apoptotic cells were quantified. Occlusion of the MCA resulted in ipsilateral cerebral infarcts in all study animals. Transfer of the bcl-2 gene resulted in high level widespread protein expression in the case of the pCMV-bcl2 plasmid, while animals treated with the pHREbcl2 vector showed lower expression levels of bcl2 which were in addition limited to the ischemic area. Treatment with pCMV-bcl2, but not with pHRE-bcl2, was able to significantly reduce the infarct volume, which was 109 ± 8 mm³ for pCMV-bcl2, 152 ± 29 mm³ for pHRE-bcl2, and 155 ± 18 mm³ for control animals. Animals transfected with either vector showed a significant reduction in numbers of apoptotic cells in the infarct and penumbra area compared with controls. There were no short-term neurological side-effects of the CSF injection of lipoplexes or of bcl-2 expression. In conclusion, the hypoxia-inducible bcl-2 expression mediated by intrathecal lipoplexes may represent a novel, biologically safe and lesion-selective therapeutic approach for neuroprotection after acute cerebral ischemia. [ABSTRACT FROM AUTHOR]

Subjects

Subjects :
*CEREBRAL ischemia
*LIPOSOMES

Details

Language :
English
ISSN :
09697128
Volume :
9
Issue :
6
Database :
Academic Search Index
Journal :
Gene Therapy
Publication Type :
Academic Journal
Accession number :
8660016
Full Text :
https://doi.org/10.1038/sj.gt.3301676