Tumor Necrosis Factor Alpha: A Link between Neuroinflammation and Excitotoxicity

Abstract EN

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.