Tumor Necrosis Factor Alpha: A Link between Neuroinflammation and Excitotoxicity

Tumor necrosis factor alpha (TNF-alpha) 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-alpha; this de novo production of TNF-alpha is an important component of the so-called neuroinflammatory response that is associated with several neurological disorders. In addition, TNF-alpha 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 GABA(A) receptors on neurons. Thus, the net effect of TNF-alpha 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-alpha 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-alpha expression is a common feature of several CNS diseases, as well as chronic opioid exposure and neuropathic pain, modulating TNF-alpha signaling may represent a valuable target for intervention.