Abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the selective loss of motor neurons. Stress activated protein kinases (SAPK) have been suggested to play a role in the pathogenesis of ALS. We studied the relevance of p38 MAPK for motor neuron degeneration in the mutant SOD1 mouse. Increased levels of phospho-p38 MAPK were present in the motor neurons and microglia of the ventral spinal cord. The p38 MAPK-inhibitor, SB203580, completely inhibited mutant SOD1-induced apoptosis of motor neurons and blocked LPS-induced activation of microglia. Semapimod, a p38 MAPK inhibitor suitable for clinical use, prolonged survival of mutant SOD1 mice to a limited extent, but largely protected motor neurons and proximal axons from mutant SOD1-induced degeneration. Our data confirm the abnormal activation of p38 MAPK in mutant SOD1 mice and the involvement of p38 MAPK in mutant SOD1-induced motor neuron death. We demonstrate the effect of p38 MAPK inhibition on survival of mutant SOD1 mice and reveal a dissociation between the effect on survival of motor neurons and that on survival of the animal, the latter likely depending on the integrity of the entire motor axon.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amyotrophic Lateral Sclerosis / drug therapy
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Amyotrophic Lateral Sclerosis / enzymology*
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Amyotrophic Lateral Sclerosis / genetics
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology
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Axons / drug effects
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Axons / enzymology
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Axons / pathology
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Cell Death / drug effects
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Cell Death / genetics
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Cell Survival / drug effects
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Cell Survival / physiology
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Enzyme Activation / drug effects
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Enzyme Activation / genetics
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Enzyme Inhibitors / pharmacology
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Hydrazones / pharmacology
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Imidazoles / pharmacology
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Mice
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Mice, Transgenic
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Motor Neurons / drug effects
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Motor Neurons / enzymology*
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Motor Neurons / pathology
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Mutation / genetics
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Nerve Degeneration / drug therapy
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Nerve Degeneration / enzymology
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Nerve Degeneration / prevention & control
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Neuroprotective Agents / pharmacology
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Pyridines / pharmacology
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Superoxide Dismutase / antagonists & inhibitors
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Superoxide Dismutase / genetics
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Superoxide Dismutase / metabolism*
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
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p38 Mitogen-Activated Protein Kinases / metabolism*
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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Enzyme Inhibitors
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Hydrazones
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Imidazoles
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Neuroprotective Agents
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Pyridines
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semapimod
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SOD1 G93A protein
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Superoxide Dismutase
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p38 Mitogen-Activated Protein Kinases
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SB 203580