The proteasome inhibitor VELCADE reduces infarction in rat models of focal cerebral ischemia.
The potential neuroprotective effects of VELCADE were investigated in two different models of focal cerebral ischemia. For time-window assessment, male Wistar-Kyoto rats were treated with 0.2 mg/kg VELCADE at 1, 2, or 3 h after the induction of permanent middle cerebral artery occlusion (MCAO) using the suture occlusion method (experiment 1). To evaluate effects in a different model, male Sprague-Dawley rats received 0.2 mg/kg VELCADE after embolic MCAO (experiment 2). Infarct volume was calculated based on TTC-staining 24 h postischemia and whole blood proteasome activity was fluorometrically determined in both experiments at baseline, 1 and 24 h post-MCAO. In experiment 1, a dose of 0.2 mg/kg inhibited proteasome activity by 77% and infarct volume was reduced to 175.7+/-59.9 mm3 and 205.9+/-83.9 mm3 (1 and 2 h group, respectively; p<0.05) compared to 306.5+/-48.5 mm3 (control). Treatment at 3 h was not neuroprotective (293.0+/-40.1 mm3). After embolic MCAO, infarct volume was 167.5+/-90.7 mm3 (treatment group) and 398.9+/-141.3 mm3 (control; p=0.002). In conclusion, VELCADE treatment inhibited whole blood proteasome activity and achieved significant neuroprotection in two rat models of focal cerebral ischemia at various time points poststroke.
Henninger
Nils
N
Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA. Nils.Henninger@umassmed.edu
Sicard
Kenneth M
KM
Bouley
James
J
Fisher
Marc
M
Stagliano
Nancy E
NE
D000818:Animals; D001897:Boronic Acids / Q000627:therapeutic use*; D000069286:Bortezomib; D020520:Brain Infarction / Q000473:pathology / Q000517:prevention & control*; D002545:Brain Ischemia / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology / Q000517:prevention & control; D020766:Intracranial Embolism / Q000473:pathology / Q000517:prevention & control; D008297:Male; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000627:therapeutic use*; D051381:Rats; D011921:Rats, Inbred WKY; D017207:Rats, Sprague-Dawley
D001897:Boronic Acids; D018696:Neuroprotective Agents; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib