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(Stroke. 2001;32:2926.)
© 2001 American Heart Association, Inc.

Original Contributions

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

Li Zhang, MD; Zheng Gang Zhang, MD; Rui Lan Zhang, MD; Mei Lu, PhD; Julian Adams, PhD; Peter J. Elliott, PhD Michael Chopp, PhD

From the Departments of Neurology (L.Z., Z.G.Z., R.L.Z., M.C.) and Biostatistics and Research Epidemiology (M.L.), Henry Ford Health System, Detroit, Mich; Millennium Pharmaceuticals Inc, Cambridge, Mass (J.A., P.J.E.); and Department of Physics, Oakland University, Rochester, Minn (M.C.).

Correspondence to Michael Chopp, PhD, Neurology Department, Henry Ford Hospital, 2799 W Grand Blvd, Detroit, MI 48202. E-mail chopp{at}neuro.hfh.edu

Background and Purpose— The proteasome inhibitor PS-519 blocks activation of nuclear factor-B, 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.

Key Words: inflammation • middle cerebral artery occlusion • tissue plasminogen activator • rats

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