Abstract
The effect of tumor necrosis factor binding protein (TNFbp) was studied in mice subjected to a permanent middle cerebral artery occlusion (MCAO). TNFbp is a dimeric form of the type I soluble TNF receptor linked to polyethylene glycol (TNFbp), and binds and inhibits TNF-alpha. TNFbp produced a significant reduction in the cortical infarct volume (22.6 +/- 3.5 mm3 immediately after MCAO; 25.2 +/- 2.4 mm3 1 h after MCAO) compared with vehicle-treated animals (30.3 +/- 3.7 mm3 immediately post MCAO; 31 +/- 3.7 mm3 1 h after MCAO (mean +/- S.D.) when administered intracranially up to 60 min post-occlusion. The neuroprotective effect of TNFbp was sustained in mice for 2 weeks after MCAO. DNA fragmentation at the margin of the cortical infarcts was dramatically reduced in mice treated with TNFbp whereas all control animals showed consistent and obvious DNA fragmentation 2 weeks after MCAO. TNFbp could have therapeutic value for the treatment of ischemic stroke if the problem of delivery to brain can be overcome.
MeSH terms
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Animals
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Arterial Occlusive Diseases / pathology
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Arterial Occlusive Diseases / therapy
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Biotin
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Brain Ischemia / pathology
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Brain Ischemia / therapy*
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Cerebral Infarction / pathology
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Cerebral Infarction / therapy
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Cyclic N-Oxides
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DNA Fragmentation
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Deoxyuracil Nucleotides
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Free Radical Scavengers / pharmacology
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Interleukin 1 Receptor Antagonist Protein
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Male
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Mice
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Mice, Inbred BALB C
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Neurons / enzymology
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Neurons / pathology
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Neuroprotective Agents / metabolism*
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Neuroprotective Agents / pharmacology
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Nitrogen Oxides / pharmacology
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Phosphopyruvate Hydratase / analysis
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Receptors, Interleukin-1 / antagonists & inhibitors
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Receptors, Tumor Necrosis Factor / metabolism*
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Receptors, Tumor Necrosis Factor, Type I
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Sialoglycoproteins / pharmacology
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Staining and Labeling
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Tumor Necrosis Factor Decoy Receptors
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Tumor Necrosis Factor-alpha / antagonists & inhibitors*
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Cyclic N-Oxides
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Deoxyuracil Nucleotides
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Free Radical Scavengers
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Il1rn protein, mouse
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Interleukin 1 Receptor Antagonist Protein
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Neuroprotective Agents
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Nitrogen Oxides
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Receptors, Interleukin-1
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Receptors, Tumor Necrosis Factor
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Receptors, Tumor Necrosis Factor, Type I
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Sialoglycoproteins
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Tumor Necrosis Factor Decoy Receptors
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Tumor Necrosis Factor-alpha
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recombinant human tumor necrosis factor-binding protein-1
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phenyl-N-tert-butylnitrone
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Biotin
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Phosphopyruvate Hydratase