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.
OBJECTIVE
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.
Zhang
Li
L
Department of Neurology, Henry Ford Health Sciences Center, Detroit, MI 48202, USA.
Zhang
Zheng Gang
ZG
Zhang
Rui Lan
RL
Lu
Mei
M
Krams
Michael
M
Chopp
Michael
M
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D039481:CD11b Antigen / Q000187:drug effects*; D002543:Cerebral Hemorrhage / Q000209:etiology / Q000473:pathology; D004195:Disease Models, Animal; D005337:Fibrin / Q000096:biosynthesis; D006023:Glycoproteins / Q000494:pharmacology* / Q000627:therapeutic use*; D015801:Helminth Proteins / Q000627:therapeutic use*; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D020766:Intracranial Embolism / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000627:therapeutic use*; D009460:Neurologic Examination; D018696:Neuroprotective Agents / Q000627:therapeutic use; D009195:Peroxidase / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000627:therapeutic use; D012720:Severity of Illness Index; D020521:Stroke / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use*
D039481:CD11b Antigen; D006023:Glycoproteins; D015801:Helminth Proteins; D008565:Membrane Proteins; D018696:Neuroprotective Agents; D011994:Recombinant Proteins; C476006:UK279276; C086581:NIF protein, Ancylostoma caninum; D005337:Fibrin; D009195:Peroxidase; D010959:Tissue Plasminogen Activator