Inhibition of p38 mitogen activated protein kinase activation and mutant SOD1G93A-induced motor neuron death

Laboratory for Neurobiology, Experimental Neurology, University of Leuven, Campus Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium.
Neurobiology of Disease (Impact Factor: 5.2). 06/2007; 26(2):332-41. DOI: 10.1016/j.nbd.2006.12.023
Source: PubMed

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.

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Available from: Ludo Van Den Bosch, Dec 19, 2013
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    • "This dysfunction appears as retraction of motor axons from neuromuscular junctions resulting in denervation and muscle weakness (Fischer et al., 2004). The pivotal significance of the axonal compartment explains the finding that preserving the cell body by interfering with the later stages of the degenerative process is insufficient to affect the clinical disease (Gould et al., 2006; Dewil et al., 2007a). "
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    • "Aberrant expression and activation of p38 MAPK have been demonstrated in motor neurons and microglia of ALS patients. Several compounds including p38 inhibitors are under investigation as potential therapeutic agents against ALS [135]. The ERK signaling pathway plays a central role in several steps of cancer development, including cancer cell migration and the development of resistance to apoptosis, such as that mediated by phosphorylation and consequent stabilization of the anti-apoptotic protein MCL-1. "
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    • "Our present results also demonstrate that in our experimental model another component of the neuronal death process is the activation of p38MAPK. As mentioned in the Introduction, it has been shown that p38MAPK is involved in other models of motor neuron degeneration, including the transgenic model of familial ALS (Tortarolo et al. 2003; Holasek et al. 2005; Veglianese et al. 2006; Dewil et al. 2007). In addition, p38MAPK is a component of a neurodegenerative processes activated by Fas that seems to be unique for motor neurons (Raoul et al. 2006). "
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