Article

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.

Download full-text

Full-text

Available from: Ludo Van Den Bosch, Dec 19, 2013
0 Followers
 · 
105 Views
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Amyotrophic lateral sclerosis is a degenerative disease affecting the motor neurons. In spite of our growing insights into its biology, it remains a lethal condition. The identification of the cause of several of the familial forms of ALS allowed generation of models to study this disease both in vitro and in vivo. Here, we summarize what is known about the pathogenic mechanisms of ALS induced by hereditary mutations, and attempt to identify the relevance of these findings for understanding the pathogenic mechanisms of the sporadic form of this disease.
    European Journal of Neuroscience 06/2010; 31(12):2247-65. DOI:10.1111/j.1460-9568.2010.07260.x · 3.67 Impact Factor
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The mammalian family of mitogen-activated protein kinases (MAPKs) includes extracellular signal-regulated kinase (ERK), p38, and c-Jun NH(2)-terminal kinase (JNK), with each MAPK signaling pathway consisting of at least three components, a MAPK kinase kinase (MAP3K), a MAPK kinase (MAP2K), and a MAPK. The MAPK pathways are activated by diverse extracellular and intracellular stimuli including peptide growth factors, cytokines, hormones, and various cellular stressors such as oxidative stress and endoplasmic reticulum stress. These signaling pathways regulate a variety of cellular activities including proliferation, differentiation, survival, and death. Deviation from the strict control of MAPK signaling pathways has been implicated in the development of many human diseases including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and various types of cancers. Persistent activation of the JNK or p38 signaling pathways has been suggested to mediate neuronal apoptosis in AD, PD, and ALS, whereas the ERK signaling pathway plays a key role in several steps of tumorigenesis including cancer cell proliferation, migration, and invasion. In this review, we summarize recent findings on the roles of MAPK signaling pathways in human disorders, focusing on cancer and neurodegenerative diseases including AD, PD, and ALS.
    Biochimica et Biophysica Acta 04/2010; 1802(4):396-405. DOI:10.1016/j.bbadis.2009.12.009 · 4.66 Impact Factor
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Vascular endothelial growth factor (VEGF) protects spinal motor neurons in models of familial amyotrophic lateral sclerosis. We previously demonstrated that VEGF also prevents motor neuron death and hindlimb paralysis in rats subjected to α-amino-3-hydroxy-5-isoxazolepropionate (AMPA)-induced chronic excitotoxic motor neuron degeneration. Here, we show that tyrosine kinase receptor-2 for VEGF (VEGFR2) is expressed in spinal motor neurons of the adult rat, and that its blockade impedes the VEGF-mediated protection against motor neuron death and paralysis. In addition, inhibition of phosphatidyl-inositol-3-kinase, which is activated by VEGFR2, completely prevented this protection, whereas blockade of mitogen-activated protein kinase kinases resulted only in a partial prevention. We show as well that AMPA induces an increased p38 mitogen-activated protein kinase (p38MAPK) phosphorylation and that VEGF blocks this effect. Furthermore, inhibition of p38MAPK prevents the paralysis induced by AMPA. These results shed light into the mechanisms of the protective effect of VEGF against excitotoxic motor neuron death in vivo and suggest that VEGFR2 and activation of phosphatidyl-inositol-3-kinase or inhibition of p38MAPK might be important therapeutic targets for amyotrophic lateral sclerosis.
    Journal of Neurochemistry 04/2010; 115(5):1090-101. DOI:10.1111/j.1471-4159.2010.06766.x · 4.24 Impact Factor
Show more