Mild Postischemic Hypothermia Prolongs the Time Window for Gene Therapy by Inhibiting Cytochrome c Release

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Abstract
Background and Purpose— We showed previously that Bcl-2 overexpression with the use of herpes simplex viral (HSV) vectors improved striatal neuron survival when delivered 1.5 hours after stroke but not when delivered 5 hours after stroke onset. Here we determine whether hypothermia prolongs the therapeutic window for gene therapy. Methods— Rats were subjected to focal ischemia for 1 hour. Hypothermia (33°C) was induced 2 hours after insult and maintained for 3 hours. Five hours after ischemia onset, HSV vectors expressing Bcl-2 plus β-gal or β-gal alone were injected into each striatum. Rats were killed 2 days later. Results— Striatal neuron survival of Bcl-2–treated, hypothermic animals was improved 2- to 3-fold over control-treated, hypothermic animals and Bcl-2–treated, normothermic animals. Neuron survival among normothermic, Bcl-2–treated animals was not different from control normothermics or control hypothermics. Double immunostaining of cytochrome c and β-gal demonstrated that Bcl-2 plus hypothermia significantly reduced cytochrome c release. Conclusions— Postischemic mild hypothermia extended the time window for gene therapy neuroprotection using Bcl-2 and reduced cytochrome c release.

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