semapimod and Amyotrophic-Lateral-Sclerosis

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.

Topics: Amyotrophic Lateral Sclerosis; Animals; Anti-Inflammatory Agents, Non-Steroidal; Axons; Cell Death; Cell Survival; Enzyme Activation; Enzyme Inhibitors; Hydrazones; Imidazoles; Mice; Mice, Transgenic; Motor Neurons; Mutation; Nerve Degeneration; Neuroprotective Agents; p38 Mitogen-Activated Protein Kinases; Pyridines; Superoxide Dismutase