Effects of hypothermia on c-fos and zif/268 gene expression following rat forebrain ischemia.

OBJECTIVE

To determine the effects of prophylactic mild hypothermia against transient forebrain ischemia, we examined the levels and localization of c-fos and zif/268 gene expression in the rat hippocampal formation at an early period during reperfusion.

METHODS

For the histochemical evaluation, Wistar rats were divided into three groups: normothermia (37 degrees C) during ischemia (n = 5), hypothermia (34 degrees C) during ischemia (n = 5), and sham-operated controls (n = 5). The former two groups were subjected to 10-min forebrain ischemia using the bilateral carotid artery occlusion with arterial hypotension (35 mmHg) technique. After 60 min of reperfusion, the brains were removed and the in situ hybridization technique was used to detect c-fos and zif/268 mRNA expression. Additionally, to determine the histopathological changes of neuronal degeneration, animals were treated with hypothermia during ischemia (n = 4) and normothermia during ischemia (n = 4). They were allowed to survive for 7 days, and then the sections of hippocampal formation were examined by light microscopy.

RESULTS

Transient ischemia increased c-fos and zif/268 mRNA signal densities from 1.8- to 6.1-fold compared with that in controls in the hippocampus. Mild hypothermia significantly inhibited the induction of c-fos and zif/268 (P < 0.01). In the CA1 subfield, hypothermia protected against delayed neuronal degeneration (P < 0.05), which was observed after normothermic ischemia.

CONCLUSIONS

The induction of transcription factor-related immediate early genes (IEGs) was a sensitive marker of the cellular response to ischemia. Mild hypothermia uniformly inhibited the induction of IEGs in the hippocampus, but the mechanisms underlying the protective effect of hypothermia against neuronal degeneration cannot be explained only by the IEGs.