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.
Kwon
Hyung-Min
HM
Department of Neurology, Seoul National University Boramae Hospital, Seoul, Korea.
Kim
YunHee
Y
Yang
Seung-In
SI
Kim
Yong-Ju
YJ
Lee
Seung-Hoon
SH
Yoon
Byung-Woo
BW
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D016227:Benzoquinones / Q000494:pharmacology* / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D001929:Brain Edema / Q000188:drug therapy* / Q000209:etiology / Q000517:prevention & control; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D019610:Cytoprotection / Q000187:drug effects* / Q000502:physiology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018840:HSP70 Heat-Shock Proteins / Q000187:drug effects* / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology; D047029:Lactams, Macrocyclic / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000187:drug effects / Q000378:metabolism; D018832:Molecular Chaperones / Q000187:drug effects / Q000378:metabolism; D009410:Nerve Degeneration / Q000188:drug therapy / Q000503:physiopathology / Q000517:prevention & control; D018696:Neuroprotective Agents / Q000494:pharmacology; D017510:Protein Folding; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology; D016896:Treatment Outcome; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D016227:Benzoquinones; D004791:Enzyme Inhibitors; D018840:HSP70 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D018832:Molecular Chaperones; D018696:Neuroprotective Agents; D020780:Matrix Metalloproteinase 9; C001277:geldanamycin