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.