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Mol Cell Neurosci. 2011 Jan;46(1):176-86. doi: 10.1016/j.mcn.2010.09.001. Epub 2010 Sep 16.

TNF-α potentiates glutamate-induced spinal cord motoneuron death via NF-κB.

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  • 1Grup de Neurobiologia Cel·lular, Institut Universitari d'Investigacions en Ciències de la Salut (IUNICS)/Departament de Biologia, Universitat de les Illes Balears, Cra. de Valldemossa km 7.5,E-07122 Palma de Mallorca, Spain.

Abstract

Besides glutamate excitotoxicity, the neuroinflammatory response is emerging as a relevant contributor to motoneuron loss in amyotrophic lateral sclerosis (ALS). In this regard, high levels of circulating proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) have been shown both in human patients and in animal models of ALS. The aim of this work was to study the effects of TNF-α on glutamate-induced excitotoxicity in spinal cord motoneurons. In rat spinal cord organotypic cultures chronic glutamate excitotoxicity, induced by the glutamate-uptake inhibitor threohydroxyaspartate (THA), resulted in motoneuron loss that was associated with a neuroinflammatory response. In the presence of TNF-α, THA-induced excitotoxic motoneuron death was potentiated. Co-exposure to TNF-α and THA also resulted in down-regulation of the astroglial glutamate transporter 1 (GLT-1) and in increased extracellular glutamate levels, which were prevented by nuclear factor-kappaB (NF-κB) inhibition. Furthermore, TNF-α and THA also cooperated in the induction of oxidative stress in a mechanism involving the NF-κB signalling pathway as well. The inhibition of this pathway abrogated the exacerbation of glutamate-mediated motoneuron death induced by TNF-α. These data link two important pathogenic mechanisms, excitotoxicity and neuroinflammation, suggested to play a role in ALS and, to our knowledge, this is the first time that TNF-α-induced NF-κB activation has been reported to potentiate glutamate excitotoxicity on motononeurons.

Copyright © 2010 Elsevier Inc. All rights reserved.

PMID:
20849956
[PubMed - indexed for MEDLINE]
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