Inhibition of p38 mitogen activated protein kinase activation and mutant SOD1(G93A)-induced motor neuron death

Neurobiol Dis. 2007 May;26(2):332-41. doi: 10.1016/j.nbd.2006.12.023. Epub 2007 Feb 6.


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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / drug therapy
  • Amyotrophic Lateral Sclerosis / enzymology*
  • Amyotrophic Lateral Sclerosis / genetics
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Axons / drug effects
  • Axons / enzymology
  • Axons / pathology
  • Cell Death / drug effects
  • Cell Death / genetics
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • Enzyme Activation / drug effects
  • Enzyme Activation / genetics
  • Enzyme Inhibitors / pharmacology
  • Hydrazones / pharmacology
  • Imidazoles / pharmacology
  • Mice
  • Mice, Transgenic
  • Motor Neurons / drug effects
  • Motor Neurons / enzymology*
  • Motor Neurons / pathology
  • Mutation / genetics
  • Nerve Degeneration / drug therapy
  • Nerve Degeneration / enzymology
  • Nerve Degeneration / prevention & control
  • Neuroprotective Agents / pharmacology
  • Pyridines / pharmacology
  • Superoxide Dismutase / antagonists & inhibitors
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase / metabolism*
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • Anti-Inflammatory Agents, Non-Steroidal
  • Enzyme Inhibitors
  • Hydrazones
  • Imidazoles
  • Neuroprotective Agents
  • Pyridines
  • semapimod
  • SOD1 G93A protein
  • Superoxide Dismutase
  • p38 Mitogen-Activated Protein Kinases
  • SB 203580