Delayed Treatment of Ischemia/Reperfusion Brain Injury Extended Therapeutic Window with the Proteosome Inhibitor MLN519

Background and Purpose— 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...