Postischemic (6-Hour) treatment with recombinant human tissue plasminogen activator and proteasome inhibitor PS-519 reduces infarction in a rat model of embolic focal cerebral ischemia.
OBJECTIVE
The proteasome inhibitor PS-519 blocks activation of nuclear factor-kappaB, a major mediator of inflammation. We tested the hypothesis that combination treatment of recombinant human tissue plasminogen activator (rhtPA) and PS-519 extends the therapeutic window for treatment of stroke with rhtPA without increasing incidence of hemorrhagic transformation.


METHODS
The middle cerebral artery (MCA) of male Wistar rats (n=56) was occluded by an embolus. After embolization, animals were randomly divided into the following groups: PS-519 treatment groups: PS-519 was given at 2, 4, or 6 hours after MCA occlusion; rhtPA treatment groups: rhtPA was given at 2 or 4 hours after MCA occlusion; combination treatment groups: PS-519 and rhtPA were given at 2, 4, or 6 hours after MCA occlusion; control group: the same volume of saline was given at 2 hours after MCA occlusion.


RESULTS
Administration of PS-519 alone at 2 or 4 hours, but not 6 hours, significantly (P<0.05) reduced infarct volume and improved neurological recovery compared with the control group. Administration of rhtPA alone at 2 hours, but not 4 hours, significantly (P<0.05) reduced infarct volume and improved neurological recovery compared with the control group. Furthermore, combination treatment with rhtPA and PS-519 even at 6 hours significantly (P<0.05) reduced infarct volume, improved neurological recovery, and did not increase the incidence of hemorrhagic transformation compared with the control group or the group treated with PS-519 alone.


CONCLUSIONS
Our data suggest that combination treatment with PS-519 and rhtPA extends the neuroprotective effect to at least 6 hours after embolization.
Zhang
L
L
Department of Neurology, Biostatistics and Research Epidemiology, Henry Ford Health System, Detroit, Michigan, USA.
Zhang
Z G
ZG
Zhang
R L
RL
Lu
M
M
Adams
J
J
Elliott
P J
PJ
Chopp
M
M
D000111:Acetylcysteine / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002452:Cell Count; D002543:Cerebral Hemorrhage / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D002544:Cerebral Infarction / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors / Q000008:administration & dosage; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D020766:Intracranial Embolism / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors; D009460:Neurologic Examination; D009195:Peroxidase / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage* / Q000009:adverse effects
D015853:Cysteine Proteinase Inhibitors; D005343:Fibrinolytic Agents; D009097:Multienzyme Complexes; C411422:PS519; D011994:Recombinant Proteins; D009195:Peroxidase; D010959:Tissue Plasminogen Activator; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D000111:Acetylcysteine