Attenuation and augmentation of ischaemia-related neuronal death by tumournecrosis factor-alpha in vitro

Upregulation of the pro-inflammatory cytokine tumour necrosis factor-alpha (TNF) occurs rapidly in the brain following ischaemia, although it is uncle ar whether this represents a neurotoxic or neuroprotective response. We hav e investigated whether TNF has different actions in the pre- and postischae mic periods in a tissue culture model of cerebral ischaemia. Organotypic hi ppocampal slice cultures were prepared from 8-10-day-old rats and maintaine d in vitro for 14 days. Neuronal damage was induced by either 1 h oxygen-gl ucose deprivation or 3 h exposure to NMDA or the superoxide generator duroq uinone, and assessed after 24 h by propidium iodide fluorescence. TNF pretr eatment was neuroprotective against both oxygen-glucose deprivation and dur oquinone. This effect was associated with an activation of the transcriptio n factor NF kappaB and upregulation of manganese superoxide dismutase, and was prevented by a free radical scavenger. When addition of TNF was delayed until the postinsult period, an exacerbation of neurotoxicity occurred, wh ich was also prevented by a free radical scavenger. The actions of TNF are determined by whether TNF is present before or after an ischaemia-related i nsult. Both actions are mediated through the production of free radicals, a nd the response to TNF is determined by whether a cell is metabolically com petent to respond by synthesis of antioxidant defences.