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: 5.08). 06/2007; 26(2):332-41. DOI: 10.1016/j.nbd.2006.12.023
Source: PubMed


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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    • "Recent studies have shown that even a complete rescue of motor neuron cell bodies does not cure mSOD1 mice [42], [43], [44] suggesting that preserving the normal function of motor neuron cells is therapeutically not sufficient, since the rescued motor neurons are unable to recreate destroyed neuromuscular junctions (NMJ) [2]. Other attempts that rescue only motor neurons have also failed to halt progression [45]. "
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    ABSTRACT: Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig's disease, is a neurodegenerative disorder of motor neurons causing progressive muscle weakness, paralysis, and eventual death from respiratory failure. There is currently no cure or effective treatment for ALS. Besides motor neuron degeneration, ALS is associated with impaired energy metabolism, which is pathophysiologically linked to mitochondrial dysfunction and glutamate excitotoxicity. The Deanna Protocol (DP) is a metabolic therapy that has been reported to alleviate symptoms in patients with ALS. In this study we hypothesized that alternative fuels in the form of TCA cycle intermediates, specifically arginine-alpha-ketoglutarate (AAKG), the main ingredient of the DP, and the ketogenic diet (KD), would increase motor function and survival in a mouse model of ALS (SOD1-G93A). ALS mice were fed standard rodent diet (SD), KD, or either diets containing a metabolic therapy of the primary ingredients of the DP consisting of AAKG, gamma-aminobutyric acid, Coenzyme Q10, and medium chain triglyceride high in caprylic triglyceride. Assessment of ALS-like pathology was performed using a pre-defined criteria for neurological score, accelerated rotarod test, paw grip endurance test, and grip strength test. Blood glucose, blood beta-hydroxybutyrate, and body weight were also monitored. SD+DP-fed mice exhibited improved neurological score from age 116 to 136 days compared to control mice. KD-fed mice exhibited better motor performance on all motor function tests at 15 and 16 weeks of age compared to controls. SD+DP and KD+DP therapies significantly extended survival time of SOD1-G93A mice by 7.5% (p = 0.001) and 4.2% (p = 0.006), respectively. Sixty-three percent of mice in the KD+DP and 72.7% of the SD+DP group lived past 125 days, while only 9% of the control animals survived past that point. Targeting energy metabolism with metabolic therapy produces a therapeutic effect in ALS mice which may prolong survival and quality of life in ALS patients.
    PLoS ONE 07/2014; 9(7):e103526. DOI:10.1371/journal.pone.0103526 · 3.23 Impact Factor
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    • "VEGF also mediates neuroprotection through the inhibition of stress activated protein kinases like p38 mitogen-activated protein kinase. Increased levels of phosphorylated p38 have been found in motor neurons and glia in the familial mouse model of ALS (Tortarolo et al., 2003; Holasek et al., 2005; Veglianese et al., 2006; Dewil et al., 2007), even at the pre-symptomatic stage (Tortarolo et al., 2003), and p38 is also an important factor in a cell death pathway specific for motor neurons (Raoul et al., 2006). Interestingly, the inhibition of p38 prevents motor neuron death in an in vitro familial model of ALS (Dewil et al., 2007), and we and others have proven that VEGF can suppress p38 activation in both familial (Tolosa et al., 2009) and excitotoxic (Tovar-Y-Romo and Tapia, 2010) models of spinal cord neurodegeneration. "
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    ABSTRACT: Motor neuron physiology and development depend on a continuous and tightly regulated trophic support from a variety of cellular sources. Trophic factors guide the generation and positioning of motor neurons during every stage of the developmental process. As well, they are involved in axon guidance and synapse formation. Even in the adult spinal cord an uninterrupted trophic input is required to maintain neuronal functioning and protection from noxious stimuli. Among the trophic factors that have been demonstrated to participate in motor neuron physiology are vascular endothelial growth factor (VEGF), glial-derived neurotrophic factor (GDNF), ciliary neurotrophic factor (CNTF) and insulin-like growth factor 1 (IGF-1). Upon binding to membrane receptors expressed in motor neurons or neighboring glia, these trophic factors activate intracellular signaling pathways that promote cell survival and have protective action on motor neurons, in both in vivo and in vitro models of neuronal degeneration. For these reasons these factors have been considered a promising therapeutic method for amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases, although their efficacy in human clinical trials have not yet shown the expected protection. In this minireview we summarize experimental data on the role of these trophic factors in motor neuron function and survival, as well as their mechanisms of action. We also briefly discuss the potential therapeutic use of the trophic factors and why these therapies may have not been yet successful in the clinical use.
    Frontiers in Cellular Neuroscience 02/2014; 8:61. DOI:10.3389/fncel.2014.00061 · 4.29 Impact Factor
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    • "In agreement with that, our group has demonstrated that VEGF protects motoneurons from serum deprivation-induced cell death through PI3-K-mediated inhibition of p38MAPK phosphorylation (Tolosa et al., 2009). Moreover, the inhibition by VEGF of p38MAPK might protect motoneurons in ALS tissue exerting a dual role both through an indirect effect on glial cells (Tortarolo et al., 2003), and a direct anti-apoptotic effect on motoneurons (Dewil et al., 2007a). "
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    ABSTRACT: Vascular endothelial growth factor (VEGF), originally described as a factor with a regulatory role in vascular growth and development, it is also known for its direct effects on neuronal cells. The discovery in the past decade that transgenic mice expressing reduced levels of VEGF developed late-onset motoneuron pathology, reminiscent of amyotrophic lateral sclerosis (ALS), opened a new field of research on this disease. VEGF has been shown to protect motoneurons from excitotoxic death, which is a relevant mechanism involved in motoneuron degeneration in ALS. Thus, VEGF delays motoneuron degeneration and increases survival in animal models of ALS. VEGF exerts its anti-excitotoxic effects on motoneurons through molecular mechanisms involving the VEGF receptor-2 resulting in the activation of the PI3-K/Akt signaling pathway, upregulation of GluR2 subunit of AMPA receptors, inhibition of p38MAPK, and induction of the anti-apoptotic molecule Bcl-2. In addition, VEGF acts on astrocytes to reduce astroglial activation and to induce the release of growth factors. The potential use of VEGF as a therapeutic tool in ALS is counteracted by its vascular effects and by its short effective time frame. More studies are needed to assess the optimal isoform, route of administration, and time frame for using VEGF in the treatment of ALS.
    Frontiers in Cellular Neuroscience 10/2013; 7(article 181):181. DOI:10.3389/fncel.2013.00181 · 4.29 Impact Factor
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