Neuroprotection achieved with a novel proteasome inhibitor which blocks NF-kappaB activation.
Activated NF-kappaB contributes to cerebral infarction by triggering a neuro-inflammatory response. Rats subjected to 90min middle cerebral artery occlusion developed a cortical infarct of 20+/-4% of hemispheric volume (n = 8). Treatment with the proteasome inhibitor CVT-634 resulted in a significantly smaller infarct of 13+/-2% (n = 7, p<0.01) and 12+/-2% (n = 8, p<0.001) of hemispheric volume at 1 day and 7 days, respectively. Since regional cerebral blood flows for the core and penumbral regions were not affected, we concluded that all animals received the same ischemic insult The reduction in infarction persisted for 7 days. This is the first indication that a proteasome inhibitor can reduce infarct volume in a focal model of cerebral ischemia.
Buchan
A M
AM
Department of Clinical Neurosciences, University of Calgary, Alberta, Canada.
Li
H
H
Blackburn
B
B
D000818:Animals; D002540:Cerebral Cortex / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002560:Cerebrovascular Circulation / Q000187:drug effects; D003546:Cysteine Endopeptidases / Q000494:pharmacology*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology*; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy*; D017078:Laser-Doppler Flowmetry; D008297:Male; D009097:Multienzyme Complexes / Q000494:pharmacology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex; D051381:Rats; D011918:Rats, Inbred SHR
C117987:5-methoxy-1-indanone-3-acetyl-leu-D-leu-1-indanylamide; D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; D009097:Multienzyme Complexes; D016328:NF-kappa B; D018696:Neuroprotective Agents; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex