title: Geldanamycin treatment during cerebral ischemia/reperfusion attenuates p44/42 mitogen-activated protein kinase activation and tissue damage.
abstract: BACKGROUND
  Heat-shock protein 90 (Hsp90) inhibitor geldanamycin was found to be neuroprotective in various experimental models of brain disease. The effect was attributed to the induction of heat-shock proteins and/or disruption of cellular signaling.
  
  
  METHODS
  In Sprague-Dawley rats, the middle cerebral artery was occluded for 90 min using the intraluminal suture method. Geldanamycin (300 mg/kg) or vehicle was injected intraperitoneally 15 min before onset of ischemia or reperfusion. Animals were sacrificed at 2, 4 or 24 h after ischemia onset and brain samples were processed for infarct volume measurement, Western blot analysis or immunofluorescent staining of Hsp90, Raf-1, p38, and p44/42 mitogen-activated protein kinases (MAPKs).
  
  
  RESULTS
  Geldanamycin treatment during ischemia or reperfusion reduced infarct volume by 79 and 61 % respectively. Geldanamycin decreased Raf-1 and activated p44/42 MAPK proteins, but did not alter levels of activated p38 MAPK during early reperfusion. Hsp90 was co-localized with Raf-1 and activated p44/42 MAPK in the cytoplasm of ischemic neurons.
  
  
  CONCLUSIONS
  Geldanamycin-induced protection against transient focal cerebral ischemia may in part be based upon depletion of Raf-1 and blockade of p44/42 MAPK activation.
authors.affiliation: Department of Neurosurgery, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Murat
authors.initials: M
authors.lastname: Karabiyikoglu
authors.forename: Ya
authors.initials: Y
authors.lastname: Hua
authors.forename: Richard F
authors.initials: RF
authors.lastname: Keep
authors.forename: Guohua
authors.initials: G
authors.lastname: Xi
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D016227:Benzoquinones / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020520:Brain Infarction / Q000517:prevention & control; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D020244:Infarction, Middle Cerebral Artery / Q000628:therapy*; D047029:Lactams, Macrocyclic / Q000627:therapeutic use*; D008297:Male; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D015428:Myocardial Reperfusion Injury / Q000150:complications / Q000188:drug therapy*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D016227:Benzoquinones; D047029:Lactams, Macrocyclic; D018696:Neuroprotective Agents; D019908:Proto-Oncogene Proteins c-raf; D048052:Mitogen-Activated Protein Kinase 3; C001277:geldanamycin