BACKGROUND AND PURPOSE: Treatment with a selective proteasome inhibitor, VELCADE, in combination with tissue plasminogen activator (tPA) extended the therapeutic window to 6 hours in young rats after stroke. However, stroke is a major cause of death and disability in the elderly. The present study investigated the effect of VELCADE in combination with a low-dose tPA on aged rats after embolic stroke. METHODS: Male Wistar rats at the age of 18 to 20 months were treated with VELCADE (0.2 mg/kg) alone, a low-dose tPA (5 mg/kg) alone, combination of VELCADE and tPA, or saline 2 hours after embolic middle cerebral artery occlusion. To test the contribution of endothelial nitric oxide synthase to VELCADE-mediated neuroprotection, endothelial nitric oxide synthase knockout and wild-type mice were treated with VELCADE (0.5 mg/kg) 2 hours after embolic stroke. RESULTS: Treatment with VELCADE significantly reduced infarct volume, whereas tPA alone did not reduce infarct volume and aggravated blood-brain barrier disruption in aged rats compared with saline-treated rats. However, the combination treatment significantly enhanced the reduction of infarct volume, which was associated with an increase in endothelial nitric oxide synthase activity compared with saline-treated rats. Additionally, the combination treatment promoted thrombolysis and did not increase the incidence of hemorrhage transformation. VELCADE significantly reduced lesion volume in wild-type mice but failed to significantly reduce lesion volume in endothelial nitric oxide synthase knockout mice. CONCLUSIONS: Treatment with VELCADE exerts a neuroprotective effect in aged rats after stroke. The combination of VELCADE with the low-dose tPA further amplifies the neuroprotective effect. Endothelial nitric oxide synthase at least partly contributes to VELCADE-mediated neuroprotection after stroke.
BACKGROUND AND PURPOSE: Treatment with a selective proteasome inhibitor, VELCADE, in combination with tissue plasminogen activator (tPA) extended the therapeutic window to 6 hours in young rats after stroke. However, stroke is a major cause of death and disability in the elderly. The present study investigated the effect of VELCADE in combination with a low-dose tPA on aged rats after embolic stroke. METHODS: Male Wistar rats at the age of 18 to 20 months were treated with VELCADE (0.2 mg/kg) alone, a low-dose tPA (5 mg/kg) alone, combination of VELCADE and tPA, or saline 2 hours after embolic middle cerebral artery occlusion. To test the contribution of endothelial nitric oxide synthase to VELCADE-mediated neuroprotection, endothelial nitric oxide synthase knockout and wild-type mice were treated with VELCADE (0.5 mg/kg) 2 hours after embolic stroke. RESULTS: Treatment with VELCADE significantly reduced infarct volume, whereas tPA alone did not reduce infarct volume and aggravated blood-brain barrier disruption in aged rats compared with saline-treated rats. However, the combination treatment significantly enhanced the reduction of infarct volume, which was associated with an increase in endothelial nitric oxide synthase activity compared with saline-treated rats. Additionally, the combination treatment promoted thrombolysis and did not increase the incidence of hemorrhage transformation. VELCADE significantly reduced lesion volume in wild-type mice but failed to significantly reduce lesion volume in endothelial nitric oxide synthase knockout mice. CONCLUSIONS: Treatment with VELCADE exerts a neuroprotective effect in aged rats after stroke. The combination of VELCADE with the low-dose tPA further amplifies the neuroprotective effect. Endothelial nitric oxide synthase at least partly contributes to VELCADE-mediated neuroprotection after stroke.
Authors: Peter U Heuschmann; Peter L Kolominsky-Rabas; Joachim Roether; Bjoern Misselwitz; Klaus Lowitzsch; Jan Heidrich; Peter Hermanek; Carsten Leffmann; Matthias Sitzer; Marcel Biegler; Hans-Joachim Buecker-Nott; Klaus Berger Journal: JAMA Date: 2004-10-20 Impact factor: 56.272
Authors: Richard LeBlanc; Laurence P Catley; Teru Hideshima; Suzanne Lentzsch; Constantine S Mitsiades; Nicholas Mitsiades; Donna Neuberg; Olga Goloubeva; Christine S Pien; Julian Adams; Deepak Gupta; Paul G Richardson; Nikhil C Munshi; Kenneth C Anderson Journal: Cancer Res Date: 2002-09-01 Impact factor: 12.701
Authors: Joan Montaner; Carlos A Molina; Jasone Monasterio; Sonia Abilleira; Juan F Arenillas; Marc Ribó; Manolo Quintana; José Alvarez-Sabín Journal: Circulation Date: 2003-02-04 Impact factor: 29.690
Authors: Victoria E O'Collins; Malcolm R Macleod; Geoffrey A Donnan; David W Howells Journal: J Cereb Blood Flow Metab Date: 2012-02-01 Impact factor: 6.200
Authors: Li Zhang; Rui Lan Zhang; Quan Jiang; Guangliang Ding; Michael Chopp; Zheng Gang Zhang Journal: Nat Protoc Date: 2015-03-05 Impact factor: 13.491