Published Online
on January 15, 2004

A more recent version of this article appeared on February 1, 2004

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Submitted on September 3, 2003
Accepted on October 14, 2003

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

Heng Zhao PhD; Midori A. Yenari MD; Robert M. Sapolsky PhD; and Gary K. Steinberg MD, PhD

From the Departments of Neurosurgery (H.Z., M.A.Y., R.M.S., G.K.S.), Biological Sciences (H.Z., R.M.S.), and Neurology and Neurological Sciences (M.A.Y., R.M.S., G.K.S.), Stanford University, Stanford, Calif.

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 -gal or -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 -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.

Key words: cerebral ischemia • gene therapy • hypothermia • ischemia, focal • proto-oncogene proteins c-bcl-2

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