Geldanamycin protects rat brain through overexpression of HSP70 and reducing brain edema after cerebral focal ischemia

OBJECTIVE: Geldanamycin (GA), a benzoquinone ansamycin, binds HSP90, releases heat shock factor 1 and induces heat shock proteins (HSPs). HSP70, a major molecular chaperone, protects the brain against ischemic injury through inhibition of apoptotic pathways in vivo and reduced matrix metalloproteinase 9 (MMP-9) after ischemia in vitro. We hypothesized that GA would protect brain from focal ischemia via induction of HSP70 and MMP suppression in vivo. METHODS: GA or vehicle was injected into the lateral cerebral ventricles of adult male Sprague-Dawley rats using the stereotatic frame 24 hours before ischemia. Rats were subjected to 2 hour middle cerebral artery occlusions using the suture technique followed by 22 hour reperfusions. One day after ischemia, we evaluated infarction volume, brain swelling, behavioral scores and immunohistochemistry. RESULTS: Western blots showed that GA at 2 mug/kg induced HSP70 by 24 hours following administration. GA decreased infarct volumes and brain edema, and improved behavioral outcomes (p<0.05). Immunohistochemistry showed that GA induced HSP70 and decreased MMP-9. DISCUSSION: GA protects brain from focal ischemia and reduces edema. This may be due, at least in part, to GA overexpression of HSP70.