Tumor Necrosis Factor Alpha: A Link between Neuroinflammation and Excitotoxicity

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; thisde novoproduction of TNF-αis an important component of the so-called neuroinflammatory response that is associated with several neurological disorders. In addition, TNF-αcan 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+2permeable-AMPA receptors and NMDA receptors, while decreasing inhibitory GABAAreceptors on neurons. Thus, the net effect of TNF-αis 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-αlinks 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-αexpression is a common feature of several CNS diseases, as well as chronic opioid exposure and neuropathic pain, modulating TNF-αsignaling may represent a valuable target for intervention.