The proteasome inhibitor VELCADE reduces infarction in rat models of focal cerebral ischemia
Department of Neurology; Graduate School of Biomedical Sciences
Animals; Boronic Acids; Brain Infarction; Brain Ischemia; Disease Models, Animal; Infarction, Middle Cerebral Artery; Intracranial Embolism; Male; Neuroprotective Agents; Proteasome Endopeptidase Complex; Pyrazines; Rats; Rats, Inbred WKY; Rats, Sprague-Dawley
Neurology | Neuroscience and Neurobiology
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.
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Citation: Neurosci Lett. 2006 May 8;398(3):300-5. Epub 2006 Feb 21. Link to article on publisher's site