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.

Abstract

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.

• Authors: Li Zhang, Zheng Gang Zhang, Rui Lan Zhang, Mei Lu, Michael Krams, Michael Chopp
• Journal: Stroke (Stroke) Vol. 34 Issue 7 Pg. 1790-5 (Jul 2003) ISSN: 1524-4628 [Electronic] United States
• PMID: 12805500 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• CD11b Antigen
• Glycoproteins
• Helminth Proteins
• Membrane Proteins
• Neuroprotective Agents
• Recombinant Proteins
• UK279276
• NIF protein, Ancylostoma caninum
• Fibrin
• Peroxidase
• Tissue Plasminogen Activator

Topics

• Animals
• Body Weight (drug effects)
• Brain (blood supply, metabolism, pathology)
• CD11b Antigen (drug effects)
• Cerebral Hemorrhage (etiology, pathology)
• Disease Models, Animal
• Fibrin (biosynthesis)
• Glycoproteins (pharmacology, therapeutic use)
• Helminth Proteins (therapeutic use)
• Humans
• Infarction, Middle Cerebral Artery (complications, drug therapy, pathology)
• Intracranial Embolism (complications, drug therapy, pathology)
• Male
• Membrane Proteins (therapeutic use)
• Neurologic Examination
• Neuroprotective Agents (therapeutic use)
• Peroxidase (biosynthesis)
• Rats
• Rats, Wistar
• Recombinant Proteins (therapeutic use)
• Severity of Illness Index
• Stroke (complications, drug therapy, pathology)
• Tissue Plasminogen Activator (therapeutic use)