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.

CONCLUSIONS

GA protects brain from focal ischemia and reduces edema. This may be due, at least in part, to GA overexpression of HSP70.