title: Delayed treatment of ischemia/reperfusion brain injury: extended therapeutic window with the proteosome inhibitor MLN519.
abstract: OBJECTIVE
  Clinical development of novel neuroprotection therapies for the treatment of brain injury has been unsuccessful. One critical limitation is the lack of a viable therapeutic treatment window (TW). In this study, we evaluated the neuroprotection TW for the proteosome inhibitor MLN519 after ischemia/reperfusion brain injury in rats as related to its antiinflammatory mechanism.
  
  
  METHODS
  Male Sprague-Dawley rats were subjected to 2 hours of middle cerebral artery occlusion (MCAo), followed by 70 hours of reperfusion and recovery. MLN519 was administered after injury (starting 6 to 12 hours after MCAo) to evaluate the full TW. Brain infarction, neuronal degeneration, neurological recovery, leukocyte infiltration, and inflammatory gene mRNA levels were assessed.
  
  
  RESULTS
  Core infarct volume in vehicle-treated rats (216+/-25 mm3) was reduced with delayed MLN519 treatments of 6, 8, or 10 hours after injury (45+/-13, 86+/-28, and 150+/-27 mm3, respectively, P<0.05) and was associated with reductions in neuronal and axonal degeneration. MLN519-treated rats had reduced brain mRNA levels of TNF-alpha (46%, P<0.05), ICAM-1 (58%, P<0.05), IL-6 (58%, P<0.05), and E-selectin (72%, P<0.05) at 24 hours after injury. Furthermore, MLN519 treatment reduced leukocyte infiltration by 32% to 80% (P<0.05) in ischemic brain regions.
  
  
  CONCLUSIONS
  Neuroprotection treatment with MLN519 provides an extended TW of up to 10 hours after ischemia/reperfusion brain injury, in part by attenuating the inflammatory response. As such, the delayed onset of brain inflammation after an ischemic injury offers a prime target for extending the neuroprotective TW with compounds such as MLN519, used either alone or possibly as an adjunctive therapy with thrombolytic agents.
authors.affiliation: Department of Neuropharmacology and Molecular Biology, Division of Neurosciences, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA. anthony.williams@na.amedd.army.mil
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Williams
authors.forename: Rossana
authors.initials: R
authors.lastname: Berti
authors.forename: Jitendra R
authors.initials: JR
authors.lastname: Dave
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Elliot
authors.forename: Julian
authors.initials: J
authors.lastname: Adams
authors.forename: Frank C
authors.initials: FC
authors.lastname: Tortella
mesh_terms: D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D015415:Biomarkers / Q000097:blood; D001923:Brain Chemistry / Q000187:drug effects; D002545:Brain Ischemia / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control*; D017024:Chemotherapy, Adjuvant; D004195:Disease Models, Animal; D019040:E-Selectin / Q000032:analysis / Q000187:drug effects; D005343:Fibrinolytic Agents / Q000627:therapeutic use; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control*; D007249:Inflammation / Q000097:blood / Q000276:immunology / Q000517:prevention & control; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000276:immunology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
chemical_list: D015415:Biomarkers; D019040:E-Selectin; D005343:Fibrinolytic Agents; D018696:Neuroprotective Agents; C411422:PS519; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D000111:Acetylcysteine