Combination Treatment With VELCADE and Low-Dose Tissue Plasminogen Activator Provides Potent Neuroprotection in Aged Rats After Embolic Focal Ischemia
- 1 May 2010
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Stroke
- Vol. 41 (5), 1001-1007
- https://doi.org/10.1161/strokeaha.109.577288
Abstract
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.This publication has 26 references indexed in Scilit:
- Plasminogen activator inhibitor type 1 derived peptide, EEIIMD, diminishes cortical infarct but fails to improve neurological function in aged rats following middle cerebral artery occlusionBrain Research, 2009
- Early disruptions of the blood–brain barrier may contribute to exacerbated neuronal damage and prolonged functional recovery following stroke in aged ratsNeurobiology of Aging, 2008
- Functional Recovery in Aged and Young Rats After Embolic StrokeStroke, 2005
- Long‐term up‐regulation of eNOS and improvement of endothelial function by inhibition of the ubiquitin–proteasome pathwayThe FASEB Journal, 2003
- Matrix metalloproteinase-9 expression in post-hypoxic human brain capillary endothelial cells: H2O2 as a trigger and NF-κB as a signal transducerThrombosis and Haemostasis, 2003
- Risk Factors for Severe Hemorrhagic Transformation in Ischemic Stroke Patients Treated With Recombinant Tissue Plasminogen ActivatorStroke, 2001
- Early Intravenous Thrombolysis for Acute Ischemic Stroke in a Community-Based ApproachStroke, 1998
- Enhancement of rabbit jugular vein thrombolysis by neutralization of factor XI. In vivo evidence for a role of factor XI as an anti-fibrinolytic factor.JCI Insight, 1998
- Tissue Plasminogen Activator for Acute Ischemic StrokeThe New England Journal of Medicine, 1995
- Characterization of the Murine Plasma Fibrinolytic SystemJBIC Journal of Biological Inorganic Chemistry, 1994