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Gene Therapy and Hypothermia for Stroke Treatment
Author(s) -
YENARI MIDORI A.,
ZHAO HENG,
GIFFARD RONA G.,
SOBEL RAYMOND A.,
SAPOLSKY ROBERT M.,
STEINBERG GARY K.
Publication year - 2003
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.2003.tb07511.x
Subject(s) - neuroprotection , hypothermia , excitotoxicity , apoptosis , cytochrome c , medicine , programmed cell death , genetic enhancement , ischemia , downregulation and upregulation , stroke (engine) , neuron , neuroscience , pharmacology , gene , biology , anesthesia , biochemistry , mechanical engineering , engineering
A bstract : We have previously reported studies of gene therapy using a neurotropic herpes simplex viral (HSV) vector system containing bipromoter vectors to transfer various protective genes to neurons. Using this system in experimental models of stroke, cardiac arrest, and excitotoxicity, we found that it is possible to enhance neuron survival against such cerebral insults by overexpressing genes that target various facets of injury. Among the genes we studied, the anti‐apoptotic protein BCL‐2 improved neuron survival following various insults, and was protective even when administered after stroke onset. BCL‐2 is thought to protect cells from apoptotic death by preventing cytochrome c release from the mitochondria and subsequent caspase activation. We and others have established that cooling the brain by a few degrees markedly reduces ischemic injury and improves neurologic deficits in models of cerebral ischemia and trauma. This hypothermic neuroprotection is also associated with BCL‐2 upregulation in some instances. Furthermore, hypothermia suppresses many aspects of apoptotic death including cytochrome c release, caspase activation, and DNA fragmentation. Here we show that two different kinds of protective therapies, BCL‐2 overexpression and hypothermia, both inhibit aspects of apoptotic cell death cascades, and that a combination treatment can prolong the temporal therapeutic window for gene therapy.