Combination treatment with VELCADE and low-dose tissue plasminogen activator provides potent neuroprotection in aged rats after embolic focal ischemia.
OBJECTIVE
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.
Zhang
Li
L
Henry Ford Health System, Department of Neurology, 2799 West Grand Boulevard, Detroit, MI 48202, USA. lzhang@neuro.hfh.edu
Zhang
Zheng Gang
ZG
Buller
Ben
B
Jiang
James
J
Jiang
Yanting
Y
Zhao
Danping
D
Liu
Xianshuang
X
Morris
Dan
D
Chopp
Michael
M
D000375:Aging / Q000187:drug effects* / Q000473:pathology; D000818:Animals; D001897:Boronic Acids / Q000008:administration & dosage*; D000069286:Bortezomib; D002545:Brain Ischemia / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D020766:Intracranial Embolism / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D011480:Protease Inhibitors / Q000008:administration & dosage; D011719:Pyrazines / Q000008:administration & dosage*; D051381:Rats; D017208:Rats, Wistar; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage*
D001897:Boronic Acids; D018696:Neuroprotective Agents; D011480:Protease Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D010959:Tissue Plasminogen Activator