Targeting tumour necrosis factor-α in hypoxia and synaptic signalling

Tumour necrosis factor (TNF)-alpha is a pro-inflammatory cytokine, which is synthesised and released in the brain by astrocytes, microglia and neurons in response to numerous internal and external stimuli. It is involved in many physiological and pathophysiological processes such as gene transcription, cell proliferation, apoptosis, synaptic signalling and neuroprotection. The complex actions of TNF-alpha in the brain are under intense investigation. TNF-alpha has the ability to induce selective necrosis of some cells whilst sparing others and this has led researchers to discover multiple activated signalling cascades. In many human diseases including acute stroke and inflammation and those involving hypoxia, levels of TNF-alpha are increased throughout different brain regions. TNF-alpha signalling may also have several positive and negative effects on neuronal function including glutamatergic synaptic transmission and plasticity. Exogenous TNF-alpha may also exacerbate the neuronal response to hypoxia. This review will summarise the actions of TNF-alpha in the central nervous system on synaptic signalling and its effects during hypoxia.