Abstract
TNF-alpha overexpression may contribute to motor neuron death in amyotrophic lateral sclerosis (ALS). We investigated the intracellular pathway associated with TNF-alpha in the wobbler mouse, a murine model of ALS, at the onset of symptoms. TNF-alpha and TNFR1 overexpression and JNK/p38MAPK phosphorylation occurred in neurons and microglia in early symptomatic mice, suggesting that this activation may contribute to motor neuron damage. The involvement of TNF-alpha was further confirmed by the protective effect of treatment with rhTNF-alpha binding protein (rhTBP-1) from 4 to 9 weeks of age. rhTBP-1 reduced the progression of symptoms, motor neuron loss, gliosis and JNK/p38MAPK phosphorylation in wobbler mice, but did not reduce TNF-alpha and TNFR1 levels. rhTBP-1 might possibly bind TNF-alpha and reduce the downstream phosphorylation of two main effectors of the neuroinflammatory response, p38MAPK and JNK.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Amyotrophic Lateral Sclerosis / genetics
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Amyotrophic Lateral Sclerosis / pathology*
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Amyotrophic Lateral Sclerosis / prevention & control*
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Animals
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Cell Count / methods
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Disease Progression
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Female
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Humans
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Male
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Mice
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Mice, Neurologic Mutants
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Motor Neurons / drug effects
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Motor Neurons / pathology*
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Motor Neurons / physiology
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Receptors, Tumor Necrosis Factor, Type I / administration & dosage
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Receptors, Tumor Necrosis Factor, Type I / therapeutic use*
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Recombinant Proteins / administration & dosage
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Recombinant Proteins / therapeutic use*
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Tumor Necrosis Factor Decoy Receptors / administration & dosage
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Tumor Necrosis Factor Decoy Receptors / therapeutic use*
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Tumor Necrosis Factor-alpha / antagonists & inhibitors
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Tumor Necrosis Factor-alpha / metabolism*
Substances
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Receptors, Tumor Necrosis Factor, Type I
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Recombinant Proteins
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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