Attenuation and augmentation of ischaemia-related neuronal death by tumour necrosis 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 unclear whether this represents a neurotoxic or neuroprotective response. We have investigated whether TNF has different actions in the pre- and postischaemic periods in a tissue culture model of cerebral ischaemia. Organotypic hippocampal slice cultures were prepared from 8-10-day-old rats and maintained in vitro for 14 days. Neuronal damage was induced by either 1 h oxygen-glucose deprivation or 3 h exposure to NMDA or the superoxide generator duroquinone, and assessed after 24 h by propidium iodide fluorescence. TNF pretreatment was neuroprotective against both oxygen-glucose deprivation and duroquinone. This effect was associated with an activation of the transcription factor NFkappaB 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, which 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 insult. Both actions are mediated through the production of free radicals, and the response to TNF is determined by whether a cell is metabolically competent to respond by synthesis of antioxidant defences.
Wilde
G J
GJ
Department of Clinical Neurological Sciences, LF73B, Level F, South Academic Block, Mailpoint 806, University of Southampton, Southampton General Hospital, Tremona Road, Southampton SO16 6YD, UK.
Pringle
A K
AK
Sundstrom
L E
LE
Mann
D A
DA
Iannotti
F
F
D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology; D016923:Cell Death; D016166:Free Radical Scavengers / Q000494:pharmacology; D002546:Ischemic Attack, Transient / Q000473:pathology / Q000503:physiopathology*; D016202:N-Methylaspartate / Q000633:toxicity*; D016328:NF-kappa B / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D009924:Organ Culture Techniques; D051381:Rats; D017208:Rats, Wistar; D017470:Receptors, Glutamate / Q000502:physiology; D013482:Superoxide Dismutase / Q000235:genetics; D013481:Superoxides / Q000633:toxicity; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D016227:Benzoquinones; D016166:Free Radical Scavengers; D016328:NF-kappa B; D017470:Receptors, Glutamate; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; D016202:N-Methylaspartate; D013482:Superoxide Dismutase; C034257:duroquinone