Gene expression after global and focal cerebral ischaemia

Inducible transcription factors (ITFs) are immediate early genes (IEGs) that regulate transcriptional processes. The pathogenetic significance of the ITE response to cerebral ischaemia is unresolved. Specific ITFs have been associated with neurotoxic and neuroprotective effects. The aims of this study were to examine the patterns of ITF expression after experimental global and focal cerebral ischaemia, to assess the expression of these genes after cerebral trauma in man, and to attempt manipulation of the ITF response using an antisense approach.Global ischaemia induced early transient ITF expression in the hippocampus. A second wave of JunB expression (72 h) was evident in regions destined to undergo delayed neuronal death (P<0.05). This delayed expression was not observed after mild ischaemia, which was not associated with cell death. After focal ischaemia, ITF expression in core ischaemic regions was generally low. However, ITF expression was pronounced in ipsilateral regions with intact CBF. A second wave of ITF expression was not observed following focal MCA occlusion at any of the time points studied. Antisense oligonucleotides did not prevent post-ischaemic ITF production or neuronal death after global ischaemia. However, in vivo neuronal uptake of biotinylated antisense molecules was not evident. Phosphothioate junB antisense protected hippocampal neurones from the effects of NMDA administration in vitro (P<0.01). ITF expression was observed in cortical tissue from all three patient groups.ITFs are expressed after both experimental cerebral ischaemia and cerebral trauma. The early expression of ITFs was confined to regions destined to survive global and focal ischaemic insults. The absence of ITF expression in core regions after focal ischaemia indicates that these factors are not prerequisites for cell death after this insult. However, the association between the second wave of JunB expression and delayed neuronal death, coupled with the neuroprotection afforded by junB antisense in cell culture suggests that, in certain milieus, JunB can promote cell death.