Inhibition of p38 mitogen activated protein kinase activation and mutant SOD1(G93A)-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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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is an adult onset degenerative disease characterized by the selective progressive death of lower and upper motor neurons. Although its primary cause remains unknown, multiple pathogenic pathways have been identified. The major pathological event in ALS is the degeneration of lower motor neurons (LMNs) and it is thought to be the ultimate cause of death. Thus neuroprotection of LMNs is assumed to be a reasonable target for treating ALS. This assumption guided most of research effort in the last 20 years to develop neuroprotective strategies able to preserve the remaining LMNs. Three major possibilities have been explored and are presented in this review. First, it is thought that LMN survival and degeneration is regulated by neurotransmittory inputs that LMN integrates. Several experimental and imaging studies have show an impairment of multiple neuronal types innervating motor neurons, in particular glycinergic interneurons, glutamatergic input from proprioceptive type Ia fibers, and serotonergic neurons. The abnormalities in glutamatergic input proved especially fruitful since they led to the discovery of riluzole. A second potential neuroprotective strategy would be to modulate neurotrophic input to motor neurons. Indeed, studies of motor neuron development have shown that their survival is governed by neurotrophic input from its muscle target or from surrounding glia. Thus, modulating neurotrophic support to LMN might be a therapeutic strategy, although the multiple clinical trials based on this possibility were up to now unsuccessful. A last possiblity to provide neuroprotection in ALS would be to indirectly modulate the motor neuron survival through action on events occuring outside this cell type, in particular inflammation or abnormal energy metabolism.
    Handbook of Neurotoxicity, Edited by Richard M. Kostrzewa, 01/2014: chapter Neuroprotective Strategies in Amyotrophic Lateral Sclerosis: Modulation of Neurotransmittory and Neurotrophic Input to Motor Neurons: pages 1417-1434; Springer., ISBN: 978-1-4614-5835-7
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    ABSTRACT: To evaluate the effects of intrathecal administration p38β antisense oligonucleotide on the development of bone cancer pain rats. Forty female SD rats weighing 180~220 g were randomly divided into 4 groups (n = 10 each): Group A (control group): intra-tibial injection of 3 μl Hank's solution; group B (model group): intra-tibial injection of 3 μl MADB-106 mammary gland carcinoma cells of rats (4.8 × 10(3)/μl); group C (p38β-SODN 20 μg); group D (p38β-ASODN 20 μg). The model procedures in group C and D were same to those in the group B. From the 14(th) day after operation, p38β-SODN 20 μg and p38β-ASODN 20 μg were respectively intrathecally administrated in group C and D once daily for 6 days whereas normal saline was for group A and B. Mechanical withdrawal threshold and radiant heat threshold of rat hind paws were measured before operation and every other day until 22 d of post-operation. The lumbar 4-6 spinal cord was removed on the 22(nd) day. The expression of spinal p38β protein was determined by Western blot. No significant differences in mechanical withdrawal threshold and radiant heat threshold were found at all time points in control group. During the first 6 days after operation there were obvious differences in radiant heat stimulus between control group between the other groups (P < 0.05); During 14-22 days after operation, mechanical pain threshold and radiant heat threshold between p38β-SODN group and Model group were significantly changed compared with that in control group (P < 0.05). However, the differences were not remarkable between control group and p38β-ASODN group (P > 0.05). The expression of p38β protein in lumbar spinal cord was significantly higher between p38β-SODN group and Model group than that in control group (P < 0.05). There was no significant difference in p38β protein expression between p38β-ASODN group and control group (P > 0.05). Hyperalgesia induced by bone cancer can be inhibited by intrathecal administration of p38β antisense oligonucleotide, which is achieved by reducing expression of p38β protein.
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    ABSTRACT: For over a century Drosophila melanogaster, commonly known as the fruit fly, has been instrumental in genetics research and disease modeling. In more recent years, it has been a powerful tool for modeling and studying neurodegenerative diseases, including the devastating and fatal amyotrophic lateral sclerosis (ALS). The success of this model organism in ALS research comes from the availability of tools to manipulate gene/protein expression in a number of desired cell-types, and the subsequent recapitulation of cellular and molecular phenotypic features of the disease. Several Drosophila models have now been developed for studying the roles of ALS-associated genes in disease pathogenesis that allowed us to understand the molecular pathways that lead to motor neuron degeneration in ALS patients. Our primary goal in this review is to highlight the lessons we have learned using Drosophila models pertaining to ALS research.
    Brain Research 10/2014; 1607. DOI:10.1016/j.brainres.2014.09.064


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May 31, 2014