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.