Published online before print June 12, 2003, doi: 10.1161/01.STR.0000077016.55891.2E
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(Stroke. 2003;34:1790.)
© 2003 American Heart Association, Inc.
Original Contributions |
Effects of a Selective CD11b/CD18 Antagonist and Recombinant Human Tissue Plasminogen Activator Treatment Alone and in Combination in a Rat Embolic Model of Stroke
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 Sciences Center, Detroit, Mich; Pfizer ClinSci CNS, Groton, Conn (M.K.); and Department of Physics, Oakland University, Rochester, Mich (M.C.).
Correspondence to Michael Chopp, PhD, Department of Neurology, Henry Ford Hospital, 2799 W Grand Blvd, Detroit, MI 48202. E-mail chopp{at}neuro.hfh.edu
Background and Purpose— We evaluated the neuroprotective effect of UK-279,276 (also referred to as recombinant neutrophil inhibitory factor), a selective CD11b/CD18 antagonist, in combination with thrombolytic therapy on focal cerebral ischemia.
Methods— Male Wistar rats (n=88) were subjected to embolic middle cerebral artery occlusion. Animals were randomly assigned to the following groups (n=11 in each group): vehicle treatment alone at 2 or 4 hours, UK-279,276 treatment alone at 2 or 4 hours, recombinant human tissue plasminogen activator (rhtPA) treatment alone at 2 or 4 hours, or the combination of UK-279,276 and rhtPA at 2 or 4 hours. Infarct volume, neurological function, hemorrhagic transformation, neutrophil accumulation, and parenchymal fibrin deposition were measured 7 days after middle cerebral artery occlusion.
Results— Treatment with UK-279,276 significantly (P<0.05) improved neurological severity scores, an index of neurological functional deficit, but had no effect on infarct volume compared with vehicle-treated animals. Treatment with rhtPA alone at 2 but not 4 hours significantly (P<0.05) reduced infarct volume and improved neurological function compared with vehicle-treated animals. Combination treatment with UK-279,276 and rhtPA at 2 or 4 hours significantly (P<0.01) reduced infarct volume and enhanced recovery of neurological function compared with control. Neutrophil accumulation and fibrin deposition in the brain parenchyma of combination-treated rats at 2 and 4 hours after stroke were significantly reduced (P<0.05) compared with corresponding vehicle-treated control groups. The neuroprotective effect of the combined treatments was superior to the additive effects from each treatment of rhtPA or UK-279,276 alone.
Conclusions— These data suggest that the combination treatment with UK-279,276 and rhtPA may extend the window of thrombolytic therapy for the acute treatment of stroke.
Key Words: neuroprotection • reperfusion injury • stroke • tissue plasminogen activator • rats
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