Delayed treatment with MLN519 reduces infarction and associated neurologic deficit caused by focal ischemic brain injury in rats via antiinflammatory mechanisms involving nuclear factor-kappaB activation, gliosis, and leukocyte infiltration.
Secondary brain injury due to ischemia includes the infiltration of leukocytes into the brain parenchyma mediated by activation of nuclear factor-kappaB (NF-kappaB), which is activated by proteasome degradation. Neuroprotection with the proteasome inhibitor MLN519 has previously been reported to decrease ischemic brain injury in rats. The authors used higher doses of MLN519 to evaluate the neuroprotection therapeutic window after 24 hours of brain injury in rats as correlated to proteasome levels, activated NF-kappaB immunoreactivity, and leukocyte infiltration. Male Sprague-Dawley rats were subjected to 2-hour middle cerebral artery occlusion (MCAO) and recovery. MLN519 or vehicle was administered after injury with a single injection given in delayed increments of 2 hours (i.e., 4, 6, or 8 hours after MCAO). Treatment with MLN519 up to 6 hours after MCAO (4 hours after reperfusion) effectively reduced neuronal and astrocytic degeneration, decreased cortical infarct volume, and increased neurologic recovery. These effects were related to >80% reductions in blood proteasome levels, reduced neutrophil infiltration, and a decrease in activated NF-kappaB immunoreactivity. This improved neuroprotection profile and antiinflammatory effect of MLN519 provides an exciting avenue for potential treatment of focal ischemic brain injury in humans.
Williams
Anthony J
AJ
Walter Reed Army Institute of Research, Silver Spring, Maryland 20910, USA. SPCAnthony.Williams@na.amedd.army.mil
Hale
Sarah L
SL
Moffett
John R
JR
Dave
Jitendra R
JR
Elliott
Peter J
PJ
Adams
Julian
J
Tortella
Frank C
FC
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D001253:Astrocytes / Q000473:pathology; D002545:Brain Ischemia / Q000150:complications* / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology; D003546:Cysteine Endopeptidases / Q000378:metabolism; D005911:Gliosis / Q000473:pathology; D020244:Infarction, Middle Cerebral Artery / Q000209:etiology* / Q000473:pathology*; D018836:Inflammation Mediators / Q000378:metabolism; D007962:Leukocytes / Q000502:physiology; D008297:Male; D009097:Multienzyme Complexes / Q000378:metabolism; D016328:NF-kappa B / Q000502:physiology; D009410:Nerve Degeneration / Q000209:etiology; D009422:Nervous System Diseases / Q000209:etiology* / Q000503:physiopathology*; D046988:Proteasome Endopeptidase Complex; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function
D018836:Inflammation Mediators; D009097:Multienzyme Complexes; D016328:NF-kappa B; C411422:PS519; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D000111:Acetylcysteine