TNF-α potentiates glutamate-induced spinal cord motoneuron death via NF-κB.
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.
Tolosa
Laia
L
Grup 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.
Caraballo-Miralles
Víctor
V
Olmos
Gabriel
G
Lladó
Jerònia
J
D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives; D016923:Cell Death / Q000187:drug effects*; D027342:Excitatory Amino Acid Transporter 2 / Q000235:genetics / Q000378:metabolism; D018698:Glutamic Acid / Q000633:toxicity*; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D009046:Motor Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D016328:NF-kappa B / Q000378:metabolism*; D009924:Organ Culture Techniques; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013116:Spinal Cord / Q000166:cytology* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D027342:Excitatory Amino Acid Transporter 2; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D001224:Aspartic Acid; D018698:Glutamic Acid