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Mediators Inflamm. 2014;2014:861231. doi: 10.1155/2014/861231. Epub 2014 May 21.

Tumor necrosis factor alpha: a link between neuroinflammation and excitotoxicity.

Author information

1
Grup de Neurobiologia Cel · lular, Departament de Biologia and Institut Universitari d'Investigacions en Ciències de la Salut, IUNICS, Universitat de les Illes Balears, 07122 Palma de Mallorca, Spain.

Abstract

Tumor necrosis factor alpha (TNF- α) is a proinflammatory cytokine that exerts both homeostatic and pathophysiological roles in the central nervous system. In pathological conditions, microglia release large amounts of TNF-α; this de novo production of TNF-α is an important component of the so-called neuroinflammatory response that is associated with several neurological disorders. In addition, TNF-α can potentiate glutamate-mediated cytotoxicity by two complementary mechanisms: indirectly, by inhibiting glutamate transport on astrocytes, and directly, by rapidly triggering the surface expression of Ca(+2) permeable-AMPA receptors and NMDA receptors, while decreasing inhibitory GABAA receptors on neurons. Thus, the net effect of TNF-α is to alter the balance of excitation and inhibition resulting in a higher synaptic excitatory/inhibitory ratio. This review summarizes the current knowledge of the cellular and molecular mechanisms by which TNF-α links the neuroinflammatory and excitotoxic processes that occur in several neurodegenerative diseases, but with a special emphasis on amyotrophic lateral sclerosis (ALS). As microglial activation and upregulation of TNF-α expression is a common feature of several CNS diseases, as well as chronic opioid exposure and neuropathic pain, modulating TNF-α signaling may represent a valuable target for intervention.

PMID:
24966471
PMCID:
PMC4055424
DOI:
10.1155/2014/861231
[Indexed for MEDLINE]
Free PMC Article

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