Postischemic (6-hour) treatment with recombinant human tissue plasminogen activator and proteasome inhibitor PS-519 reduces infarction in a rat modelof embolic focal cerebral ischemia

Background mid Purpose-The proteasome inhibitor PS-519 blocks activation of nuclear factor-kappaB, a major mediator of inflammation. We tested the hyp othesis 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 transforma tion. Methods-The middle cerebral artery (MCA) of male Wistar rats (n=56) was occ luded by an embolus. After embolization, animals were randomly divided into the following croups: PS-519 treatment groups: PS-519 was given at 2, 4, o r 6 hours after MCA occlusion rhtPA treatment groups: rhtPA was given at 2 or 4 hours after MCA occlusions combination treatment groups: PS-519 and rh tPA 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. si gnificantly (P <0.05) reduced infarct volume and improved neurological reco very compared with the control group. Administration of rhtPA alone at 2 ho urs, but not 4 hours, significantly (P <0.05) reduced infarct volume and im proved 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 no t increase the incidence of hemorrhagic transformation compared with the co ntrol group or the group treated with PS-519 alone. Conclusions-Our data suggest that combination treatment with PS-5 19 and rh tPA extends the neuroprotective effect to at least 6 hours after embolizati on.